Substituted Diaza-Spiro-[5.5]-Undecane Derivaties and Their Use as Neurokinin Antagonists

ABSTRACT

This invention concerns substituted diaza-spiro-[5.5]-undecane derivatives having neurokinin antagonistic activity, in particular NK 1  antagonistic activity, a combined NK 1 /NK 2  antagonistic activity, a combined NK 1 /NK 3  antagonistic activity and a combined NK 1 /NK 2 /NK 3  antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment and/or prophylaxis of schizophrenia, emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain, in particular visceral and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, COPD and micturition disorders such as urinary incontinence. 
 
The compounds according to the invention can be represented by general Formula (I)  
                 
and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

FIELD OF THE INVENTION

This invention concerns substituted diaza-spiro-[5.5]-undecanederivatives having neurokinin antagonistic activity, in particular NK₁antagonistic activity, a combined NK₁/NK₂ antagonistic activity, acombined NK₁/NK₃ antagonistic activity and a combined NK₁/NK₂/NK₃antagonistic activity, their preparation, compositions comprising themand their use as a medicine, in particular for the treatment and/orprophylaxis of schizophrenia, emesis, anxiety and depression, irritablebowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia,nociception, pain, in particular visceral and neuropathic pain,pancreatitis, neurogenic inflammation, asthma, chronic obstructivepulmonary disease (COPD) and micturition disorders such as urinaryincontinence.

BACKGROUND OF THE INVENTION

Tachykinins belong to a family of short peptides that are widelydistributed in the mammalian central and peripheral nervous system(Bertrand and Geppetti, Trends Pharmacol. Sci. 17:255-259 (1996);Lundberg, Can. J. Physiol. Pharmacol. 73:908-914 (1995); Maggi, Gen.Pharmacol. 26:911-944 (1995); Regoli et al., Pharmacol. Rev. 46 (1994)).They share the common C-terminal sequence Phe-Xaa-Gly-Leu-Met-NH₂.Tachykinins released from peripheral sensory nerve endings are believedto be involved in neurogenic inflammation. In the spinal cord/centralnervous system, tachykinins may play a role in paintransmission/perception and in some autonomic reflexes and behaviors.The three major tachykinins are Substance P (SP), Neurokinin A (NKA) andNeurokinin B (NKB) with preferential affinity for three distinctneurokinin receptor subtypes, termed NK₁, NK₂, and NK₃, respectively.However, functional studies on cloned receptors suggest strongfunctional cross-interaction between the 3 tachykinins and theircorresponding neurokinin receptors (Maggi and Schwartz, TrendsPharmacol. Sci. 18: 351-355 (1997)).

Species differences in structure of NK₁ receptors are responsible forspecies-related potency differences of NK₁ antagonists (Maggi, Gen.Pharmacol. 26:911-944 (1995); Regoli et al., Pharmacol. Rev.46(4):551-599 (1994)). The human NK₁ receptor closely resembles the NK₁receptor of guinea-pigs and gerbils but differs markedly from the NK₁receptor of rodents. The development of neurokinin antagonists has ledto date to a series of peptide compounds of which might be anticipatedthat they are metabolically too labile to be employed aspharmaceutically active substances (Longmore J. et al., DN&P 8(1):5-23(1995)).

The tachykinins are involved in schizophrenia, depression,(stress-related) anxiety states, emesis, inflammatory responses, smoothmuscle contraction and pain perception. Neurokinin antagonists are indevelopment for indications such as emesis, anxiety and depression,irritable bowel syndrome (IBS), circadian rhythm disturbances, visceralpain, neurogenic inflammation, asthma, micturition disorders, andnociception. In particular, NK₁ antagonists have a high therapeuticpotential in emesis and depression and NK₂ antagonists have a hightherapeutic potential in asthma treatments. NK₃ antagonists seem to playa role in the treatment of pain/inflammation (Giardina, G. et al. Exp.Opin. Ther. Patents, 10(6): 939-960 (2000)) and schizophrenia.

Schizophrenia

The NK3 antagonist SR142801 (Sanofi) was recently shown to haveantipsychotic activity in schizophrenic patients without affectingnegative symptoms (Arvantis, L. ACNP Meeting, December 2001). Activationof NK₁ receptors causes anxiety, stressful events evoke elevatedsubstance P (SP) plasma levels and NK₁ antagonists are reported to beanxiolytic in several animal models. The NK₁ antagonist from Merck,MK-869 shows antidepressant effects in major depression, but data werenot conclusive due to a high placebo response rate. Moreover, the NK₁antagonist from Glaxo-Welcome (S)-GR205,171 was shown to enhancedopamine release in the frontal cortex but not in the striatum (Lejeuneet al. Soc. Neurosci., November 2001). It is therefore hypothesized thatNK₃ antagonism in combination with NK₁ antagonism would be beneficialagainst both positive and negative symptoms of schizophrenia.

Anxiety and Depression

Depression is one of the most common affective disorders of modernsociety with a high and still increasing prevalence, particularly in theyounger members of the population. The life time prevalence rates ofMajor depression (MDD, DSM-IV) is currently estimated to be 10-25% forwomen and 5-12% for men, whereby in about 25% of patients the life timeMDD is recurrent, without full inter-episode recovery and superimposedon dysthymic disorder. There is a high co-morbidity of depression withother mental disorders and, particularly in younger population highassociation with drug and alcohol abuse. In the view of the fact thatdepression primarily affects the population between 18-44 years of agee.g. the most productive population, it is obvious that it imposes ahigh burden on individuals, families and the whole society.

Among all therapeutic possibilities, the therapy with antidepressants isincontestably the most effective. A large number of antidepressants havebeen developed and introduced to the market in the course of the last 40years. Nevertheless, none of the current antidepressants fulfill allcriteria of an ideal drug (high therapeutic and prophylactic efficacy,rapid onset of action, completely satisfactory short- and long-termsafety, simple and favourable pharmacokinetics) or is without sideeffects which in one or the other way limits their use in all groups andsubgroups of depressed patients.

Since no treatment of the cause of depression exists at present, norappears imminent, and no antidepressant is effective in more than 60-70%of patients; the development of a new antidepressant which maycircumvent any of the disadvantages of the available drugs is justified.

Several findings indicate involvement of SP in stress-related anxietystates. Central injection of SP induces a cardiovascular responseresembling the classical “fight or flight” reaction characterisedphysiologically by vascular dilatation in skeletal muscles and decreaseof mesenteric and renal blood flow. This cardiovascular reaction isaccompanied by a behavioral response observed in rodents after noxiousstimuli or stress (Culman and Unger, Can. J Physiol. Pharmacol.73:885-891 (1995)). In mice, centrally administered NK₁ agonists andantagonists are anxiogenic and anxiolytic, respectively (Teixeira etal., Eur. J. Pharmacol. 311:7-14 (1996)). The ability of NK₁ antagoniststo inhibit thumping induced by SP (or by electric shock; Ballard et al.,Trends Pharmacol. Sci. 17:255-259 (2001)) might correspond to thisantidepressant/anxiolytic activity, since in gerbils thumping plays arole as an alerting or warning signal to conspecifics.

The NK₁ receptor is widely distributed throughout the limbic system andfear-processing pathways of the brain, including the amygdala,hippocampus, septum, hypothalamus, and periaqueductal grey.Additionally, substance P is released centrally in response to traumaticor noxious stimuli and substance P-associated neuro-transmission maycontribute to or be involved in anxiety, fear, and the emotionaldisturbances that accompany affective disorders such as depression andanxiety. In support of this view, changes in substance P content indiscrete brain regions can be observed in response to stressful stimuli(Brodin et al., Neuropeptides 26:253-260 (1994)).

Central injection of substance P mimetics (agonists) induces a range ofdefensive behavioral and cardiovascular alterations includingconditioned place aversion (Elliott, Exp. Brain. Res. 73:354-356(1988)), potentiated acoustic startle response (Krase et al., Behav.Brain. Res. 63:81-88 (1994)), distress vocalisations, escape behaviour(Kramer et al., Science 281:1640-1645 (1998)) and anxiety on theelevated plus maze (Aguiar and Brandao, Physiol. Behav. 60:1183-1186(1996)). These compounds did not modify motor performance andco-ordination on the rotarod apparatus or ambulation in an activitycage. Down-regulation of substance P biosynthesis occurs in response tothe administration of known anxiolytic and antidepressant drugs (Brodinet al., Neuropeptides 26:253-260 (1994); Shirayama et al., Brain. Res.739:70-78 (1996)). Similarly, a centrally administered NK₁agonist-induced vocalisation response in guinea-pigs can be antagonizedby antidepressants such as imipramine and fluoxetine as well asL-733,060, an NK₁ antagonist. These studies provide evidence suggestingthat blockade of central NK₁ receptors may inhibit psychological stressin a manner resembling antidepressants and anxiolytics (Rupniak andKramer, Trends Pharmacol. Sci. 20:1-12 (1999)), but without the sideeffects of present medications.

Emesis

Nausea and vomiting are among the most distressing side effects ofcancer chemotherapy. These reduce the quality of life and may causepatients to delay or refuse, potentially curative drugs (Kris et al., J.Clin. Oncol., 3:1379-1384 (1985)). The incidence, intensity and patternof emesis is determined by different factors, such as thechemotherapeutic agent, dosage and route of administration. Typically,early or acute emesis starts within the first 4 h after chemotherapyadministration, reaching a peak between 4 h and 10 h, and decreases by12 to 24 h. Delayed emesis (developing after 24 h and continuing until3-5 days post chemotherapy) is observed with most ‘high-emetogenic’chemotherapeutic drugs (level 4 and 5 according to Hesketh et al., J.Clin. Oncol. 15:103 (1997)). In humans, these ‘high-emetogenic’anti-cancer treatments, including cis-platinum, induce acute emesisin >98% and delayed emesis in 60-90% of cancer patients.

Animal models of chemotherapy such as cisplatin-induced emesis inferrets (Rudd and Naylor, Neuropharmacology 33:1607-1608 (1994); Naylorand Rudd, Cancer. Surv. 21:117-135 (1996)) have successfully predictedthe clinical efficacy of the 5-HT₃ receptor antagonists. Although thisdiscovery led to a successful therapy for the treatment of chemotherapy-and radiation-induced sickness in cancer patients, 5-HT₃ antagonistssuch as ondansetron and granisetron (either or not associated withdexamethasone) are effective in the control of the acute emetic phase(the first 24 h) but can only reduce the development of delayed emesis(>24 h) with poor efficacy (De Mulder et al., Annuals of InternalMedicine 113:834-840 (1990); Roila, Oncology 50:163-167 (1993)). Despitethese currently most effective treatments for the prevention of bothacute and delayed emesis, still 50% of patients suffer from delayedvomiting and/or nausea (Antiemetic Subcommittee, Annals Oncol. 9:811-819(1998)).

In contrast to 5-HT₃ antagonists, NK₁ antagonists such as CP-99,994(Piedimonte et al., L. Pharmacol. Exp. Ther. 266:270-273 (1993)) andaprepitant (also known as MK-869 or L-754,030; Kramer et al., Science281:1640-1645 (1998); Rupniak and Kramer, Trends Pharmacol. Sci. 20:1-12(1999)) have now been shown to inhibit not only the acute but also thedelayed phase of cisplatin-induced emesis in animals (Rudd et al., Br.J. Pharmacol. 119:931-936 (1996); Tattersall et al., Neuropharmacology39:652-663 (2000)). NK₁ antagonists have also been demonstrated toreduce ‘delayed’ emesis in man in the absence of concomitant therapy(Cocquyt et al., Eur. J. Cancer 37:835-842 (2001); Navari et al., N.Engl. L. Med. 340:190-195 (1999)). When administered together withdexamethasone and 5-HT₃ antagonists, moreover, NK₁ antagonists (such asMK-869 and CJ-11,974, also known as Ezlopitant) have been shown toproduce additional effects in the prevention of acute emesis (Campos etal., J. Clin. Oncol. 19:1759-1767 (2001); Hesketh et al., Clin. Oncol.17:338-343 (1999)).

Central neurokinin NK₁ receptors play a major role in the regulation ofemesis. NK₁ antagonists are active against a wide variety of emeticstimuli (Watson et al., Br. J. Pharmacol. 115:84-94 (1995); Tattersallet al., Neuropharmacol. 35:1121-1129 (1996); Megens et al., J.Pharmacol. Exp. Ther. 302:696-709 (2002)). The compounds are suggestedto act by blocking central NK₁-receptors in the nucleus tractussolitarius. Apart from NK₁ antagonism CNS penetration is thus aprerequisite for the antiemetic activity of these compounds.Loperamide-induced emesis in ferrets can be used as a fast and reliablescreening model for the antiemetic activity of NK₁ antagonists. Furtherevaluation of their therapeutic value in the treatment of both the acuteand the delayed phases of cisplatin-induced emesis has been demonstratedin the established ferret model (Rudd et al., Br. J. Pharmacol.119:931-936 (1994)). This model studies both ‘acute’ and ‘delayed’emesis after cisplatin and has been validated in terms of itssensitivity to 5-HT₃ receptor antagonists, glucocorticoids (Sam et al.,Eur. J. Pharmacol. 417:231-237 (2001)) and other pharmacologicalchallenges. It is unlikely that any future anti-emetic would findclinical acceptance unless successfully treating both the ‘acute’ and‘delayed’ phases of emesis.

Visceral Pain and Irritable Bowel Syndrome (IBS)

Visceral sensation refers to all sensory information that originates inthe viscera (heart, lungs, GI tract, hepatobiliary tract and urogenitaltract), and is transmitted to the central nervous system resulting inconscious perception. Both the vagal nerve via the nodose ganglion andthe primary sympathetic afferent nerves via dorsal root ganglias (DRG)and second order neurons in the dorsal horn serve as the initialpathways along which visceral sensory information is conveyed to thebrain stem and to the viscero-somatic cortex. Visceral pain may becaused by neoplastic processes (e.g. pancreas cancer), inflammation(e.g. cholecystitis, peritonitis), ischemia and mechanical obstruction(e.g. urether stone).

The mainstay of medical treatment for visceral pain linked to organicdisorders (in casu cancer of the viscera) still focuses on opiates.

Recent evidence suggests that non-organic visceral disorders such asirritable bowel syndrome (IBS), non-cardiac chest pain (NCCP) andchronic pelvic pain may originate from a state of “visceral hyperalgia”.The latter is defined as a condition in which physiological, non-painfulvisceral stimuli (e.g. gut distension) lead to conscious perception ofpain due to a decreased threshold for pain. Visceral hyperalgesia mayreflect a state of a permanent, post-inflammatory resetting of thethreshold for membrane depolarization at neuronal synapses withinvisceral sensory pathways. The initial inflammation may occur at theperiphery (e.g. infectious gastroenteritis) or at the site of visceralsensory information integration (neurogenic inflammation in the dorsalhorn). Both SP and calcitonin gene-related peptide (CGRP) have beenshown to act as pro-inflammatory neuropeptides in neurogenicinflammation.

Visceral hyperalgesia is currently considered as one of the primetargets for drug development aimed at treating functional boweldiseases, which occur in 15 to 25% of the western population. Theyconstitute an enormous socio-economic problem in terms of medical carecosts, prescription costs and absenteism. Current treatment optionsinclude anti-spasmodics (IBS and NCCP), promotility agents (e.g.tegasorod in constipation-IBS), laxatives (constipation-IBS), andloperamide (diarrhea-IBS), amongst others. None of these approaches hasbeen shown to be very effective, particularly in treating pain. Low dosetricyclic antidepressants and SSRIs are used to treat visceralhyperalgesia in pain-predominant IBS, but both classes of compounds mayhave considerable effects on colonic transit. Ongoing research in thisfield has identified a considerable number of molecular targets thatcould serve for drug development in visceral hyperalgesia. These includeNK receptors, the CGRP receptor, 5-HT₃ receptors, glutamate receptors,and the kappa opioid receptor. Ideally, a “visceral analgesic compound”should block heightened sensory transfer from the viscera to the CNSwithout affecting the normal physiological homeostasis of the GI tractwith regards to propulsive motor activity, absorption and secretion, andsensation. There is compelling evidence linking tachykinin to visceralnociceptive signalling. A number of pre-clinical publications on therole of NK₁, NK₂ and NK₃ receptors in visceral pain and visceralhyperalgesia indicate a discrepancy between the implication of NK₁, NK₂and NK₃ receptors in the different inflammation hypersensitivity rodentmodels. Recently, Kamp et al., J. Pharmacol. Exp. Ther.299:105-113(2001) suggested that a combined neurokinin receptor antagonist could bemore active than a selective neurokinin receptor antagonist. Substance Pand NK₁, NK₂ and NK₃ receptors are elevated in clinical pain states,including visceral pain states (Lee et al., Gastroenterol. 118: A846(2000)). Given the recent failures of NK₁ receptor antagonists as ananalgesic in human pain trials (Goldstein et al., Clin. Pharm. Ther.67:419-426 (2000)), combinations of antagonists may be necessary to havea significant clinical effect. NK₃ receptor antagonists areanti-hyperalgesic (Julia et al., Gastroenterol. 116:1124-1131 (1999));J. Pharmacol. Exp. Ther.299:105-113 (2001)). Recently, the involvementof NK₁ and NK₃ receptors but not NK₂ receptors at spinal level wasdemonstrated in visceral hypersensitivity mediated by nociceptive andnon-nociceptive afferent inputs (Gaudreau & Ploudre, Neurosci. Lett.351:59-62 (2003). Combining the NK₁₋₂₋₃ antagonistic activity couldtherefore represent an interesting therapeutic target for thedevelopment of novel treatments for visceral hyperalgesia.

A reasonable number of pre-clinical publications over the role of NK₁receptors in visceral pain has been published. Using NK₁ receptorknockout mice and NK₁ antagonists in animal models, different groupshave demonstrated the important role played by the NK₁ receptor inhyperalgesia and visceral pain. The distribution of NK₁ receptors andsubstance P favors a major role in visceral rather than in somatic pain.Indeed more than 80% of visceral primary afferent contain substance Pcompared with only 25% skin afferents. NK₁ receptors are also involvedin gastrointestinal motility (Tonini et al., Gastroenterol. 120:938-945(2001); Okano et al., J. Pharmacol. Exp. Ther. 298:559-564 (2001)).Because of this dual role in both gastrointestinal motility and innociception, NK₁ antagonists are considered to have potential toameliorate symptoms in IBS patients.

Urinary Incontinence

Urge urinary incontinence is caused by urinary bladder or detrusorhyperreflexia (“irritable bladder”). This hyperreflexia relates tohyperexcitability of bladder sensory afferent C-fibers projecting to thespinal cord. The origin of C-fiber hyperexcitability is multifactorialbut occurs for example after bladder infection and chronic distention ofthe bladder wall (eg. benign prostate hypertrophy, BPH). Hence,treatment should be aimed at decreasing neuronal hyperexcitability.Intravesical instillation of vanilloids (eg. capsaicin) results in along-term beneficial effect on detrusor hyperreflexia refractory toconventional treatment with anticholinergic drugs. Analogous to animalstudies, the effect of vanilloids is mediated through a neurotoxiceffect on sensory nerve terminals. In human bladder, subendothelialsensory nerves contain tachykinins, which drive detrusorhyperexcitability. The NK receptors involved in this effect areperipheral NK₂ receptors and to a lesser extent, also NK₁ receptors. Thelatter are claimed to play a role in bladder hyperreflexia at the levelof the spinal cord. As a consequence, a centrally actingNK₁/peripherally acting NK₂ antagonist is preferred for the treatment ofdetrusor hyperexcitability. Interestingly, activation of NK₂ receptorsincreases aromatase activity in Sertoli cells. NK₂ receptor antagonistsreduce serum testosterone levels in mice, and this may be of therapeuticimportance in BPH.

BACKGROUND PRIOR ART

Compounds containing a piperidinyl-moiety, substituted by a piperidinylor pyrrolidinyl-moiety were published in WO97/24324 (Jul. 10, 1997), WO97/24350 (Jul. 10, 1997) and WO97/24356 (Jul. 10, 1997), all by JanssenPharmaceutica N. V. for use as substance P (neurokinin) antagonists.Compounds comprising a substituted diaza-spiro[4.5]decanyl-moiety werepublished in WO01/94346 (Dec. 13, 2001) by F. Hoffmann-La Roche AG foruse as neurokinin receptor antagonists.

The compounds of the present invention differ structurally from thecompounds of the prior art in that the compounds of the presentinvention all comprise a piperidinyl-moiety substituted with adiaza-spiro[5.5]undecanyl moiety as well as in their improved ability aspotent, orally and centrally active neurokinin antagonists withtherapeutic value, especially for the treatment and/or prophylaxis ofschizophrenia, emesis, anxiety and depression, irritable bowel syndrome(IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain,in particular visceral and neuropathic pain, pancreatitis, neurogenicinflammation, asthma, COPD and micturition disorders such as urinaryincontinence.

DESCRIPTION OF THE INVENTION

The present invention relates to novel substituteddiaza-spiro-[5.5]-undecane derivatives according to the general Formula(I)

the pharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof, the N-oxide form thereof andprodrugs thereof, wherein:

-   R² is Ar², Ar²-alkyl, di(Ar²)alkyl, Het¹ or Het¹-alkyl;-   X is a covalent bond or a bivalent radical of formula —O—, —S— or    —NR³—;-   Q is O or NR³;-   each R³ independently from each other, is hydrogen or alkyl;-   R¹ is selected from the group of Ar¹, Ar¹-alkyl and di(Ar¹)-alkyl;-   n is an integer, equal to 0, 1 or 2;-   m is an integer, equal to 1 or 2, provided that if m is 2, then n is    1;-   Z is a covalent bond or a bivalent radical of formula —CH₂— or    >C(═O);-   j, k, p, q are integers, independently from each other equal to 0,    1, 2, 3 or 4; provided that each of (j+k) and (p+q) is equal to 4;-   T is ═O in an alpha-position relative to the N-atom and t is an    integer, equal to 0 or 1;-   each Alk represents, independently from each other, a covalent bond;    a bivalent straight or branched, saturated or unsaturated    hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic    saturated or unsaturated hydrocarbon radical having from 3 to 6    carbon atoms; each radical optionally substituted on one or more    carbon atoms with one or more, phenyl, halo, cyano, hydroxy, formyl    and amino radicals;-   Y is a covalent bond or a bivalent radical of formula —C(═O)—,    —SO₂—>C═CH—R or >C═N—R, wherein R is H, CN or nitro;-   L is selected from the group of hydrogen, alkyl, alkenyl, alkyloxy,    alkyloxyalkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, mono- and    di(alkyl)amino, mono- and di(alkyloxycarbonyl)amino, mono- and    di(alkylcarbonyl)amino, mono-and di(Ar³)amino, mono-and    di(Ar³alkyl)amino, mono-and di(Het²)amino, mono-and    di(Het²alkyl)amino, alkylsulfanyl, norbornyl, adamantyl,    tricycloundecyl, Ar³, Ar³-oxy, Ar³carbonyl, Het², Het-oxy,    Het²carbonyl and mono- and di(Het²carbonyl)amino;-   Ar¹ is phenyl, optionally substituted with 1, 2 or 3 substituents,    each independently from each other, selected from the group of halo,    alkyl, cyano, aminocarbonyl and alkyloxy;-   Ar² is naphthalenyl or phenyl, each optionally substituted with 1, 2    or 3 substituents, each independently from each other, selected from    the group of halo, nitro, amino, mono- and di(alkyl)amino, cyano,    alkyl, hydroxy, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl    and mono- and di(alkyl)aminocarbonyl;-   Ar³ is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3    substituents, each independently from each other, selected from the    group of alkyloxy, alkylcarbonylamino, methanesulfonyl,    Ar¹carbonyloxyalkyl, Ar¹alkyloxycarbonyl, Ar¹alkyloxyalkyl, alkyl,    halo, hydroxy, pyridinyl, morpholinyl, pyrrolyl, pyrrolidinyl,    imidazo[1,2-a]pyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl,    amino and cyano;-   Het¹ is a monocyclic heterocyclic radical selected from the the    group of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl,    pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocyclic    radical selected from the group of quinolinyl, quinoxalinyl,    indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,    benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl,    indanyl and chromenyl; wherein each mono- and bicyclic heterocyclic    radical may optionally be substituted on any atom by one or more    radicals, each independently from each other, selected from the    group of halo, oxo and alkyl;-   Het² is a monocyclic heterocyclic radical selected from the group of    pyrrolidinyl, dihydro-2H-pyranyl, pyranyl, dioxolyl, imidazolidinyl,    tetrahydropyridinyl, tetrahydropyrimidinyl, pyrazolidinyl,    piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl,    imidazolidinyl, tetrahydrofuranyl, 2H-pyrrolyl, pyrrolinyl,    imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl,    triazolyl, furanyl, thienyl, oxazolyl, dioxazolyl, oxazolidinyl,    isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridinyl,    1H-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl and    tetrazolyl;    -   or a bicyclic heterocyclic radical selected from the group of        2,3-dihydro-benzo[1,4]dioxine, octahydro-benzo[1,4]dioxine,        octabicycloheptyl, benzopiperidinyl, quinolinyl, quinoxalinyl,        indolyl, isoindolyl, chromanyl, benzimidazolyl,        imidazo[1,2-a]pyridinyl, benzoxazolyl, benzodioxolyl,        benzisoxazolyl, benzoxadiazolyl, benzothiazolyl,        benzisothiazolyl, benzofuranyl, dihydroisobenzofuranyl, or        benzothienyl; wherein each mono-, and bicyclic heterocyclic        radical may optionally be substituted on any atom with one or        more radicals selected from the group of Ar¹, Ar¹alkyl,        Ar¹alkyloxyalkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl,        thienyl, oxo, alkyloxy, alkylcarbonyl, Ar¹carbonyl, mono- and        di(alkyl)aminoalkyl, alkyloxyalkyl and alkyloxycarbonyl;-   alkyl is a straight or branched saturated hydrocarbon radical having    from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals    having from 3 to 6 carbon atoms; each hydrocarbon radical optionally    substituted on one or more carbon atoms with one or more radicals    selected from the group of phenyl, halo, trihalomethyl,    aminocarbonyl, methyl, ethyl, propyl, isopropyl, t-butyl, cyano,    oxo, hydroxy, formyl and amino; and-   alkenyl is a straight or branched unsaturated hydrocarbon radical    having from 1 to 6 carbon atoms and having 1 or more unsaturated    bonds; or a cyclic unsaturated hydrocarbon radical having from 3 to    6 carbon atoms and having 1 or more unsaturated bonds; each    hydrocarbon radical optionally substituted on one or more carbon    atoms with one or more radicals selected from the group of phenyl,    halo, cyano, oxo, hydroxy, formyl and amino.

More in particular, the invention relates to a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and a prodrug thereof, wherein:

-   R² is Ar², Ar²-alkyl or Het¹;-   X is a covalent bond;-   Q is O;-   R¹ is Ar¹-alkyl;-   n is an integer, equal to 1;-   m is an integer, equal to 1;-   Z is a covalent bond or a bivalent radical of formula —CH₂— or    >C(═O);-   j, k, p, q are integers, independently from each other equal to 1, 2    or 3 ; provided that (j+k) and (p+q) are equal to 4;-   t is an integer, equal to 0 or 1;-   each Alk represents, independently from each other, a covalent bond;    a bivalent straight or branched, saturated or unsaturated    hydrocarbon radical having from 1 to 6 carbon atoms; or a cyclic    saturated or unsaturated hydrocarbon radical having from 3 to 6    carbon atoms; each radical optionally substituted with an hydroxy    radical;-   Y is a covalent bond or a bivalent radical of formula —C(═O)— or    —SO₂—;-   L is selected from the group of hydrogen, alkyl, alkenyl, alkyloxy,    norbornyl, tricycloundecyl, Ar³, Ar³-oxy, Het² and mono- and    di(Het²carbonyl)amino;-   Ar¹ is phenyl, optionally substituted with 2 halo-radicals;-   Ar² is naphthalenyl or phenyl, each optionally substituted with 1, 2    or 3 substituents, each independently from each other, selected from    the group of halo, cyano, alkyl and alkyloxy;-   Ar³ is phenyl, optionally substituted with 1 substituent, selected    from the group of alkyloxy, alkylcarbonylamino, methanesulfonyl,    alkyl, halo, pyrrolyl and cyano;-   Het¹ is a monocyclic heterocyclic radical selected from the the    group of pyrrolyl, furanyl, thienyl, pyridinyl and pyrazinyl; or a    bicyclic heterocyclic radical selected from the group of quinolinyl    and indolyl; wherein each mono- and bicyclic heterocyclic radical    may optionally be substituted on any atom by one or more alkyl    radicals;-   Het² is a monocyclic heterocyclic radical selected from the group of    pyrrolidinyl, dihydro-2H-pyranyl, pyranyl, tetrahydropyridinyl,    tetrahydropyrimidinyl, pyrrolyl, imidazolyl, furanyl, thienyl,    oxazolidinyl, isoxazolyl, thiadiazolyl, pyridinyl, 1H-pyridinyl,    pyrazinyl, pyridazinyl and tetrazolyl;    -   or a bicyclic heterocyclic radical selected from the group of        octabicycloheptyl, quinoxalinyl, benzimidazolyl, benzodioxolyl,        benzoxadiazolyl, benzofuranyl or dihydroisobenzofuranyl; wherein        each mono- and bicyclic heterocyclic radical may optionally be        substituted on any atom with one or more radicals selected from        the group of halo, alkyl, oxo and alkyloxycarbonyl;-   alkyl is a straight or branched saturated hydrocarbon radical having    from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicals    having from 3 to 6 carbon atoms; each hydrocarbon radical optionally    substituted on one or more carbon atoms with one or more radicals    selected from the group of trihalomethyl, aminocarbonyl, methyl,    t-butyl and cyano, and-   alkenyl is a cyclic unsaturated hydrocarbon radical having from 3 to    6 carbon atoms and having 1 unsaturated bond.

More in particular, the invention relates to a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and a prodrug thereof, wherein the spiro-moiety hasone of the following chemical formulas (f1)-(f9), wherein all variablesare defined as in Formula (I) and “a” denotes the piperidinyl-moiety ofFormula (I) and “b” denotes the Alk-Y-Alk-L-moiety of Formula (I):

More in particular, the invention relates to a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and a prodrug thereof, wherein the spiro-moiety hasthe Formula (f1) (wherein j, k, p and q are equal to 2), f2 (wherein jand k are equal to 2; and p is equal to 1 and q is equal to 3) and f12(wherein j and q are equal to 1 and k and p are equal to 3).

More in particular, the-invention relates to a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and a prodrug thereof, wherein R¹ is Ar¹methyl andattached to the 2-position or R¹ is Ar¹ and attached to the 3-position,as exemplified in either of the following formulas for compoundsaccording to Formula (I) wherein m and n are equal to 1 and Ar is anunsubstituted phenyl. Preferably, Ar¹methyl is a benzyl radical.

More in particular, the invention relates to a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and a prodrug thereof, wherein the R²—X—C(=Q)-moiety is 3,5-di-(trifluoromethyl)phenylcarbonyl.

More in particular, the invention relates to a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and a prodrug thereof, wherein m and n are bothequal to 1.

More in particular, the invention relates to a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and a prodrug thereof, wherein Y is —C(═O)—.

More in particular, the invention relates to a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and a prodrug thereof, wherein Alk is a covalentbond or —CH₂—.

More in particular, the invention relates to a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and a prodrug thereof, wherein L is cyclopropyl.

More in particular, the invention relates to a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and a prodrug thereof, wherein the compound is acompound with compound number 132, 100, 92, 93, 3, 4 and 119, asdescribed in any one of Tables 1-7 further in this application.

In the framework of this application, alkyl is defined as a monovalentstraight or branched saturated hydrocarbon radical having from 1 to 6carbon atoms, for example methyl, ethyl, propyl, butyl, 1-methylpropyl,1,1-dimethylethyl, pentyl, hexyl; alkyl further defines a monovalentcyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms,for example cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. The definition of alkyl also comprises an alkyl radical thatis optionally substituted on one or more carbon atoms with one or morephenyl, halo, cyano, oxo, hydroxy, formyl and amino radicals, forexample hydroxyalkyl, in particular hydroxymethyl and hydroxyethyl andpolyhaloalkyl, in particular difluoromethyl and trifluoromethyl.

In the framework of this application, alkenyl is defined as a monovalentstraight or branched unsaturated hydrocarbon radical having from 1 to 6carbon atoms and having 1 or more unsaturated bonds, for examplemethenyl, ethenyl, propenyl, butenyl, 1-methylpropenyl,1,1-dimethylethenyl, pentenyl and hexenyl; alkenyl further defines amonovalent cyclic unsaturated hydrocarbon radical having from 3 to 6carbon atoms and having 1 or more unsaturated bonds, for examplecyclopropenyl, methyl-cyclopropenyl, cyclobutenyl, cyclopentenyl andcyclohexenyl. The definition of alkenyl also comprises an alkenylradical that is optionally substituted on one or more carbon atoms withone or more radicals selected from the group of phenyl, halo, cyano,oxo, hydroxy, formyl and amino radicals, for example hydroxyalkenyl, inparticular hydroxyethenyl and hydroxyethyl and polyhaloalkyl, inparticular difluoromethyl and trifluoromethyl.

In the framework of this application, halo is generic to fluoro, chloro,bromo and iodo.

In the framework of this application, with “compounds according to theinvention” is meant a compound according to the general Formula (I), thepharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof, the N-oxide form thereof and aprodrug thereof.

In the framework of this application, especially in the moietyAlk^(a)-Y-Alk^(b) in Formula (I), when two or more consecutive elementsof said moiety denote a covalent bond, then a single covalent bond isdenoted. For example, when Alk^(a) and Y denote both a covalent bond andAlk^(b) is —CH₂—, then the moiety Alk^(a)-Y-Alk^(b) denotes —CH₂—.Similary, if Alk^(a), Y and Alk^(b) each denote a covalent bond and Ldenotes H, then the moiety Alk^(a)-Y-Alk^(b)-L denotes —H.

The pharmaceutically acceptable salts are defined to comprise thetherapeutically active non-toxic acid addition salts forms that thecompounds according to Formula (I) are able to form. Said salts can beobtained by treating the base form of the compounds according to Formula(I) with appropriate acids, for example inorganic acids, for examplehydrohalic acid, in particular hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid and phosphoric acid; organic acids, forexample acetic acid, hydroxyacetic acid, propanoic acid, lactic acid,pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid,fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

The compounds according to Formula (I) containing acidic protons mayalso be converted into their therapeutically active non-toxic metal oramine addition salts forms by treatment with appropriate organic andinorganic bases. Appropriate base salts forms comprise, for example, theammonium salts, the alkaline and earth alkaline metal salts, inparticular lithium, sodium, potassium, magnesium and calcium salts,salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine,hybramine salts, and salts with amino acids, for example arginine andlysine.

Conversely, said salts forms can be converted into the free forms bytreatment with an appropriate base or acid.

The term addition salt as used in the framework of this application alsocomprises the solvates that the compounds according to Formula (I) aswell as the salts thereof, are able to form. Such solvates are, forexample, hydrates and alcoholates.

The N-oxide forms of the compounds according to Formula (I) are meant tocomprise those compounds of Formula (I) wherein one or several nitrogenatoms are oxidized to the so-called N-oxide, particularly those N-oxideswherein one or more tertiary nitrogens (e.g of the piperazinyl orpyrrolidinyl radical) are N-oxidized. Such N-oxides can easily beobtained by a skilled person without any inventive skills and they areobvious alternatives for the compounds according to Formula (I) sincethese compounds are metabolites, which are formed by oxidation in thehuman body upon uptake. As is generally known, oxidation is normally thefirst step involved in drug metabolism (Textbook of Organic Medicinaland Pharmaceutical Chemistry, 1977, pages 70-75). As is also generallyknown, the metabolite form of a compound can also be administered to ahuman instead of the compound per se, with possibly the same effects.

The compounds according to the invention possess at least 2 oxydizablenitrogens (tertiary amines moieties). It is therefore highly likely thatN-oxides will form in the human metabolism.

The compounds of Formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the staring material of Formula (I) with anappropriate organic or inorganic-peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydroperoxide. Suitable solvents are, for example, water,lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms that the compounds of Formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms having that designation, said mixturescontaining all diastereomers and enantiomers of the basic molecularstructure. More in particular, stereogenic centers may have the R— orS-configuration; substituents on bivalent cyclic (partially) saturatedradicals may have either the cis- or trans-configuration. Compoundsencompassing double bonds can have an E or Z-stereochemistry at saiddouble bond. Stereochemically isomeric forms of the compounds of Formula(I) are obviously intended to be embraced within the scope of thisinvention.

Following CAS nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a molecule, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. R* and S* eachindicate optically pure stereogenic centers with undetermined absoluteconfiguration. If “α” and “β” are used: the position of the highestpriority substituent on the asymmetric carbon atom in the ring systemhaving the lowest ring number, is arbitrarily always in the “α” positionof the mean plane determined by the ring system. The position of thehighest priority substituent on the other asymmetric carbon atom in thering system (hydrogen atom in compounds according to Formula (I))relative to the position of the highest priority substituent on thereference atom is denominated “α”, if it is on the same side of the meanplane determined by the ring system, or “β”, if it is on the other sideof the mean plane determined by the ring system.

Compounds according to Formula (I) and some of the intermediatecompounds have at least two stereogenic centers in their structure.

The invention also comprises derivative compounds (usually called“pro-drugs”) of the pharmacologically-active compounds according to theinvention, which are degraded in vivo to yield the compounds accordingto the invention. Pro-drugs are usually (but not always) of lowerpotency at the target receptor than the compounds to which they aredegraded. Pro-drugs are particularly useful when the desired compoundhas chemical or physical properties that make its administrationdifficult or inefficient. For example, the desired compound may be onlypoorly soluble, it may be poorly transported across the mucosalepithelium, or it may have an undesirably short plasma half-life.Further discussion on pro-drugs may be found in Stella, V. J. et al.,“Prodrugs”, Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985,29, pp. 455-473.

Pro-drugs forms of the pharmacologically-active compounds according tothe invention will generally be compounds according to Formula (I), thepharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof and the N-oxide form thereof,having an acid group which is esterified or amidated. Included in suchesterified acid groups are groups of the formula —COOR^(x), where R^(x)is a C₁₋₆alkyl, phenyl, benzyl or one of the following groups:

Amidated groups include groups of the formula —CONR^(y)R^(x), whereinR^(y) is H, C₁₋₆alkyl, phenyl or benzyl and R^(z) is —OH, H, C₁₋₆alkyl,phenyl or benzyl. Compounds according to the invention having an aminogroup may be derivatised with a ketone or an aldehyde such asformaldehyde to form a Mannich base. This base will hydrolyze with firstorder kinetics in aqueous solution.

The compounds of Formula (I) as prepared in the processes describedbelow may be synthesized in the form of racemic mixtures of enantiomersthat can be separated from one another following art-known resolutionprocedures. The racemic compounds of Formula (I) may be converted intothe corresponding diastereomeric salt forms by reaction with a suitablechiral acid Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of Formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound would be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

Pharmacology

Substance P and other tachykinins are involved in a variety ofbiological actions such as pain transmission (nociception), neurogenicinflammation, smooth muscle contraction, plasma protein extravasation,vasodilation, secretion, mast cell degranulation, and also in activationof the immune system. A number of diseases are deemed to be engenderedby activation of neurokinin receptors, in particular the NK₁ receptor,by excessive release of substance P and other neurokinins in particularcells such as cells in the neuronal plexi of the gastrointestinal tract,unmyelinated primary sensory afferent neurons, sympathetic andparasympathetic neurons and nonneuronal cell types (DN&P 8(1):5-23(1995) and Longmore J. et al., “Neurokinin Receptors” PharmacologicalReviews 46(4):551-599 (1994)).

The compounds of the present invention are potent inhibitors ofneurokinin-mediated effects, in particular those mediated via the NK₁,NK₂ and NK₃ receptor, and may therefore be described as neurokininantagonists, especially as substance P antagonists, as may be indicatedin vitro by the antagonism of substance P-induced relaxation of pigcoronary arteries. The binding affinity of the present compounds for thehuman, guinea-pig and gerbil neurokinin receptors may also be determinedin vitro in a receptor binding test using ³H-substance-P as radioligand.The subject compounds also show substance-P antagonistic activity invivo as may be evidenced by, for instance, the antagonism of substanceP-induced plasma extravasation in guinea-pigs, or the antagonism ofdrug-induced emesis in ferrets (Watson et al., Br. J. Pharmacol.115:84-94 (1995)).

In view of their capability to antagonize the actions of tachykinins byblocking the neurokinin receptors, and in particular by blocking theNK₁, NK₂ and NK3 receptor, the compounds according to the invention areuseful as a medicine, in particular in the prophylactic and therapeutictreatment of tachykinin-mediated conditions. In particular are compoundsaccording to the invention are useful as orally active, centrallypenetrating medicines in the prophylactic and therapeutic treatment oftachykinin-mediated conditions.

More in particular, it has been found that some compounds exhibit acombined NK₁/NK₂ antagonistic activity, a combined NK₁/NK₃ antagonisticactivity or a combined NK₁/NK₂/NK₃ antagonistic activity—as can be seenfrom Table 10 in the experimental section.

The invention therefore relates to a compound according to the generalFormula (I), the pharmaceutically acceptable acid or base addition saltsthereof, the stereochemically isomeric forms thereof, the N-oxide formthereof and prodrugs thereof, for use as a medicine.

The invention also relates to the use of a compound according to thegeneral Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and prodrugs thereof for the manufacture of amedicament for treating, either prophylactic or therapeutic or both,tachykinin mediated conditions.

The compounds according to the invention are useful in the treatment ofCNS disorders, in particular schizoaffective disorders, depression,anxiety disorders, stress-related disorders, sleep disorders, cognitivedisorders, personality disorders, eating disorders, neurodegenerativediseases, addiction disorders, mood disorders, sexual dysfunction,visceral pain and other CNS-related conditions; inflammation; allergicdisorders; emesis; gastrointestinal disorders, in particular irritablebowel syndrome (IBS); skin disorders; vasospastic diseases; fibrosingand collagen diseases; disorders related to immune enhancement orsuppression and rheumatic diseases and body weight control.

In particular, the compounds according to the invention are useful inthe treatment or prevention of schizoaffective disorders resulting fromvarious causes, including schizoaffective disorders of the manic type,of the depressive type, of mixed type; paranoid, disorganized,catatonic, undifferentiated and residual schizophrenia; schizophreniformdisorder; delusional disorder; brief psychotic disorder; sharedpsychotic disorder; substance-induced psychotic disorder; and psychoticdisorder not otherwise specified.

In particular, the compounds according to the invention are useful inthe treatment or prevention of depression including but not limited tomajor depressive disorders including bipolar depression; unipolardepression; single or recurrent major depressive episodes with orwithout psychotic features, catatonic features, melancholic features,atypical features or postpartum onset, and, in the case of recurrentepisodes, with or without seasonal pattern. Other mood disordersencompassed within the term “major depressive disorder” includedysthymic disorder with early or late onset and with or without atypicalfeatures, bipolar I disorder, bipolar II disorder, cyclothymic disorder,recurrent brief depressive disorder, mixed affective disorder, neuroticdepression, post traumatic stress disorder and social phobia; dementiaof the Alzheimer's type with early or late onset, with depressed mood;vascular dementia with depressed mood; substance-induced mood disorderssuch as mood disorders induced by alcohol, amphetamines, cocaine,hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics,anxiolytics and other substances; schizoaffective disorder of thedepressed type; and adjustment disorder with depressed mood. Majordepressive disorders may also result from a general medical conditionincluding, but not limited to, myocardial infarction, diabetes,miscarriage or abortion, etc.

In particular, the compounds according to the invention are useful inthe treatment or prevention of anxiety disorders, including but notlimited to panic attack; agoraphobia; panic disorder withoutagoraphobia; agoraphobia without history of panic disorder; specificphobia; social phobia; obsessive-compulsive disorder; post-traumaticstress disorder; acute stress disorder; generalized anxiety disorder;anxiety disorder due to a general medical condition; substance-inducedanxiety disorder; and anxiety disorder not otherwise specified.

In particular, the compounds according to the invention are useful inthe treatment or prevention of stress-related disorders associated withdepression and/or anxiety, including but not limited to acute stressreaction; adjustment disorders, such as brief depressive reaction,prolonged depressive reaction, mixed anxiety and depressive reaction,adjustment disorder with predominant disturbance of other emotions,adjustment disorder with predominant disturbance of conduct, adjustmentdisorder with mixed disturbance of emotions and conduct and adjustmentdisorders with other specified predominant symptoms; and other reactionsto severe stress.

In particular, the compounds according to the invention are useful inthe treatment or prevention of sleep disorders, including but notlimited to dysomnia and/or parasomnias as primary sleep disorders;insomnia; sleep apnea; narcolepsy; circadian rhythms disorders; sleepdisorders related to another mental disorder; sleep disorder due to ageneral medical condition; and substance-induced sleep disorder.

In particular, the compounds according to the invention are useful inthe treatment or prevention of cognitive disorders, including but notlimited to dementia; amnesic disorders and cognitive disorders nototherwise specified, especially dementia caused by degenerativedisorders, lesions, trauma, infections, vascular disorders, toxins,anoxia, vitamin deficiency or endocrinic disorders; dementia of theAlzheimer's type, with early or late onset, with depressed mood;AIDS-associated dementia or amnesic disorders caused by alcohol or othercauses of thiamin deficiency, bilateral temporal lobe damage due toHerpes simplex encephalitis and other limbic encephalitis, neuronal losssecondary to anoxia/hypoglycemia/severe convulsions and surgery,degenerative disorders, vascular disorders or pathology around ventricleIII. Furthermore, the compounds according to the invention are alsouseful as memory and/or cognition enhancers in healthy humans with nocognitive and/or memory deficit.

In particular, the compounds according to the invention are useful inthe treatment or prevention of personality disorders, including but notlimited to paranoid personality disorder; schizoid personality disorder;schizotypical personality disorder; antisocial personality disorder;borderline personality disorder; histrionic personality disorder;narcissistic personality disorder; avoidant personality disorder;dependent personality disorder; obsessive-compulsive personalitydisorder and personality disorder not otherwise specified.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of eating disorders, including anorexianervosa; atypical anorexia nervosa; bulimia nervosa; atypical bulimianervosa; overeating associated with other psychological disturbances;vomiting associated with other psychological disturbances; andnon-specified eating disorders.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of neurodegenerative diseases, includingbut not limited to Alzheimer's disease; Huntington's chorea;Creutzfeld-Jacob disease; Pick's disease; demyelinating disorders, suchas multiple sclerosis and ALS; other neuropathies and neuralgia;multiple sclerosis; amyotropical lateral sclerosis; stroke and headtrauma.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of addiction disorders, including but notlimited to substance dependence or abuse with or without physiologicaldependence, particularly where the substance is alcohol, amphetamines,amphetamine-like substances, caffeine, cocaine, hallucinogens,inhalants, nicotine, opioids (such as cannabis, heroin and morphine),phencyclidine, phencyclidine-like compounds, sedative-hypnotics,benzodiazepines and/or other substances, particularly useful fortreating withdrawal from the above substances and alcohol withdrawaldelirium.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of mood disorders induced particularly byalcohol, amphetamines, caffeine, cannabis, cocaine, hallucinogens,inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics,anxiolytics and other substances.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of sexual dysfunction, including but notlimited to sexual desire disorders; sexual arousal disorders; orgasmicdisorders; sexual pain disorders; sexual dysfunction due to a generalmedical condition; substance-induced sexual dysfunction and sexualdysfunction not otherwise specified.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of pain, including but not limited totraumatic pain such as postoperative pain; traumatic avulsion pain suchas brachial plexus; chronic pain such as arthritic pain such asoccurring in osteo-rheumatoid or psoriatic arthritis; neuropathic painsuch as post-herpetic neuralgia, trigeminal neuralgia, segmental orintercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy,diabetic neuropathy, chemotherapy-induced neuropathy, AIDS relatedneuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngealneuralgia, reflex sympathetic dystrophy and phantom limb pain; variousforms of headache such as migraine, acute or chronic tension headache,temporomandibular pain, maxillary sinus pain and cluster headache;odontalgia; cancer pain; visceral pain; gastrointestinal pain; nerveentrapment pain; sport's injury pain; dysmennorrhoea; menstrual pain;meningitis; arachnoiditis; musculoskeletal pain; low back pain such asspinal stenosis, prolapsed disc, sciatica, angina, ankylosingspondyolitis; gout; burns; scar pain; itch; and thalamic pain such aspost stroke thalamic pain.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of the following other CNS-relatedconditions: akinesia, alinetic-rigid syndromes, dyskinesia andmedication-induced parkinsonism, Gilles de la Tourette syndrome and itssymptoms, tremor, chorea, myoclonus, tics and dystonia,attention-deficit/hyperactivity disorder (ADHD), Parkinson's disease,drug-induced Parkinsonism, post-encephalitic Parkinsonism, progressivesupranuclear palsy, multiple system atrophy, corticobasal degeneration,parkinsonism-ALS dementia complex and basal ganglia calcification,behavioral disturbances and conduct disorders in dementia and thementally retarded, including restlessness and agitation, extra-pyramidalmovement disorders, Down's syndrome and Akathisia.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of inflammation, including but notlimited to inflammatory conditions in asthma, influenza, chronicbronchitis and rheumatoid arthritis; inflammatory conditions in thegastrointestinal tract such as, but not limited to Crohn's disease,ulcerative colitis, inflammatory bowel disease and non-steroidalanti-inflammatory drug induced damage; inflammatory conditions of theskin such as herpes and eczema; inflammatory conditions of the bladdersuch as cystitis and urge incontinence; eye and dental inflammation andpancreatitis, in particular chronic and acute pancreatitis.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of allergic disorders including but notlimited to allergic disorders of the skin such as but not limited tourticaria; and allergic disorders of the airways such as but not limitedto rhinitis.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of emesis, i.e. nausea, retching andvomiting, including but not limited to acute emesis, delayed emesis andanticipatory emesis; emesis induced by drugs such as cancerchemotherapeutic agents such as alkylating agents, for examplecyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxicantibiotics, for example dactinomycin, doxorubicin, mitomycin-C andbleomycin; anti-metabolites, for example cytarabine, methotrexate and5-fluorouracil; vinca alkaloids, for example etoposide, vinblastine andvincristine; and other drugs such as cisplatin, dacarbazine,procarbazine and hydroxyurea; and combinations thereof; radiationsickness; radiation therapy, such as in the treatment of cancer;poisons; toxins such as toxins caused by metabolic disorders or byinfection, such as gastritis, or released during bacterial or viralgastrointestinal infection; pregnancy; vestibular disorders, such asmotion sickness, vertigo, dizziness and Meniere's disease;post-operative sickness; gastrointestinal obstruction; reducedgastrointestinal motility; visceral pain, such as myocardial infarctionor peritonitis; migraine; increased intracranial pressure; decreasedintracranial pressure (such as altitude sickness); opioid analgesics,such as morphine; gastro-oesophageal reflux disease; acid indigestion;over-indulgence of food or drink; acid stomach; sour stomach;waterbrash/regurgitation; heartburn, such as episodic heartburn,nocturnal heartburn and meal induced heartburn; and dyspepsia.

In particular, the compounds according to the invention are also usefulin the treatment or prevention of gastrointestinal disorders, includingbut not limited to irritable bowel syndrome (IBS), skin disorders suchas psoriasis, pruritis and sunburn; vasospastic diseases such as angina,vascular headache and Reynaud's disease, cerebral ischaemia such ascerebral vasospasm following subarachnoid haemorrhage; fibrosing andcollagen diseases such as scleroderma and eosinophilic fascioliasis;disorders related to immune enhancement or suppression such as systemiclupus erythematosus and rheumatic diseases such as fibrositis; cough;and body weight control, including obesity.

Most in particular, the compounds according to the invention are alsouseful for the manufacture of a medicament for the treatment and/orprophylaxis of schizophrenia, emesis, anxiety and depression, irritablebowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia,nociception, pain, in particular visceral and neuropathic pain,pancreatitis, neurogenic inflammation, asthma, chronic obstructivepulmonary disease (COPD) and micturition disorders such as urinaryincontinence.

The present invention also relates to a method for the treatment and/orprophylaxis of schizophrenia, emesis, anxiety and depression, irritablebowel syndrome (IBS), circadian rhythm disturbances, pre-eclampsia,nociception, pain, in particular visceral and neuropathic pain,pancreatitis, neurogenic inflammation, asthma, chronic obstructivepulmonary disease (COPD) and micturition disorders such as urinaryincontinence, comprising administering to a human in need of suchadministration an effective amount of a compound according to theinvention, in particular according to Formula (I), the pharmaceuticallyacceptable acid or base addition salts thereof, the stereochemicallyisomeric forms thereof, the N-oxide form thereof, as well as thepro-drugs thereof.

The invention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier and, as active ingredient, atherapeutically effective amount of a compound according to theinvention, in particular a compound according to Formula (I), thepharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof, the N-oxide form thereof and aprodrug thereof.

The compounds according to the invention, in particular the compoundsaccording to Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and the prodrugs thereof, or any subgroup orcombination thereof may be formulated into various pharmaceutical formsfor administration purposes. As appropriate compositions there may becited all compositions usually employed for systemically administeringdrugs. To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, optionally in addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, in particular, for administration orally,rectally, percutaneously, by parenteral injection or by inhalation. Forexample, in preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations that are intended tobe converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

Since the compounds according to the invention are potent orally, mainlycentrally active NK₁, NK₁/NK₂, NK₁/NK₃ and NK₁/NK₂/NK₃ antagonists,pharmaceutical compositions comprising said compounds for administrationorally are especially advantageous.

Synthesis

The compounds according to the invention can generally be prepared by asuccession of steps, each of which is known to the skilled person.

The final compounds of Formula (Ia) are conveniently prepared byreductively N-alkylating an intermediate compound of Formula (II) withan intermediate compound of Formula (III). Said reductive N-alkylationmay be performed in a reaction-inert solvent such as, for example,dichloromethane, ethanol or toluene or a mixture thereof, and in thepresence of an appropriate reducing agent such as, for example, aborohydride, e.g. sodium borohydride, sodium cyanoborohydride ortriacetoxy borohydride. In case a borohydride is used as a reducingagent, it may be convenient to use a complex-forming agent such as, forexample, titanium(IV)isopropylate as described in J. Org. Chem, 1990,55, 2552-2554. Using said complex-forming agent may also result in animproved cis/trans ratio in favor of the trans isomer. It may also beconvenient to use hydrogen as a reducing agent in combination with asuitable catalyst such as, for example, palladium-on-charcoal orplatinum-on-charcoal. In case hydrogen is used as reducing agent, it maybe advantageous to add a dehydrating agent to the reaction mixture suchas, for example, aluminium tert-butoxide. In order to prevent theundesired further hydrogenation of certain functional groups in thereactants and the reaction products, it may also be advantageous to addan appropriate catalyst-poison to the reaction mixture, e.g., thiopheneor quinoline-sulphur. Stirring and optionally elevated temperaturesand/or pressure may enhance the rate of the reaction.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, trituration and chromatography.

The final compounds of Formula (Ib) are conveniently prepared byreductively N-alkylating an intermediate compound of Formula (V) with anintermediate compound of Formula (III). Said reductive N-alkylation maybe performed in a reaction-inert solvent such as, for example,dichloromethane, ethanol or toluene or a mixture thereof, and in thepresence of an appropriate reducing agent such as, for example, aborohydride, e.g. sodium borohydride, sodium cyanoborohydride ortriacetoxy borohydride. In case a borohydride is used as a reducingagent, it may be convenient to use a complex-forming agent such as, forexample, titanium(IV)iso-propylate as described in J. Org. Chem, 1990,55, 2552-2554. It may also be convenient to use hydrogen as a reducingagent in combination with a suitable catalyst such as, for example,palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is usedas reducing agent, it may be advantageous to add a dehydrating agent tothe reaction mixture such as, for example, aluminium tert-butoxide. Inorder to prevent the undesired further hydrogenation of certainfunctional groups in the reactants and the reaction products, it mayalso be advantageous to add an appropriate catalyst-poison to thereaction mixture, e.g., thiophene or quinoline-sulphur. Stirring andoptionally elevated temperatures and/or pressure may enhance the rate ofthe reaction.

The final compounds of Formula (Ic) are conveniently prepared byreacting a carboxylic acid compound of Formula (V) with an intermediatecompound of Formula (III). The reaction can be performed in areaction-inert solvent such as, for example, a chlorinated hydrocarbon,e.g. dichloromethane, in the presence of a suitable base such as, forexample, sodium carbonate, sodium hydrogen carbonate or triethylamineand in the presence of an activator, such as e.g. DCC(dicyclohexylcarbodiimide), CDI (carbonyldiimidazole) and EDCI(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl). Stirring mayenhance the rate of the reaction. The reaction may conveniently becarried out at a temperature ranging between room temperature and refluxtemperature.

Especially advantageous is the preparation of a final compound accordingto any of Formulas (Ia), (Ib) and (Ic) and according to the previouslymentioned reaction schemes wherein a compound according to Formula (II),(IV) or (V) is reacted with a compound according to Formula (III) inwhich the Alk-Y-Alk-L-moiety is benzyl (Formula (XI)), thus giving riseto a compound wherein the Alk-Y-Alk-L-moiety is benzyl. Said finalcompound is pharmacologically active and can be converted into a finalcompound according to Formula (I′) in which the Alk-Y-Alk-L-moiety ishydrogen by reductive hydrogenation using e.g. hydrogen as a reducingagent in combination with a suitable catalyst such as, for example,palladium-on-charcoal or platinum-on-charcoal. The resulting finalcompound according to the invention can then be converted into othercompounds according to Formula (I) by art-known transformations, e.g.acylation and alkylation.

In particular, the final compounds of Formula (Id) can be prepared byreacting a final compound of Formula (I′) with an intermediate compoundof Formula (VI) wherein W¹ is an appropriate leaving group such as, forexample, a halogen, e.g. chloro or bromo, or a sulfonyloxy leavinggroup, e.g. methanesulfonyloxy or benzenesulfonyloxy. The reaction canbe performed in a reaction-inert solvent such as, for example, achlorinated hydrocarbon, e.g. dichloromethane or a ketone, e.g. methylisobutylketone, and in the presence of a suitable base such as, forexample, sodium carbonate, sodium hydrogen carbonate or triethylamine.Stirring may enhance the rate of the reaction. The reaction mayconveniently be carried out at a temperature ranging between roomtemperature and reflux temperature.

Alternatively, the final compounds of Formula (Id) can also be preparedby reacting a final compound of Formula (I′) with a carboxylic acid ofFormula (VII). The reaction can be performed in a reaction-inert solventsuch as, for example, a chlorinated hydrocarbon, e.g. dichloromethane,in the presence of a suitable base such as, for example, sodiumcarbonate, sodium hydrogen carbonate or triethylamine and in thepresence of an activator, such as e.g. DCC (dicyclohexylcarbodiimide),CDI (carbonyl-diimidazole) and EDCI(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. HCl). Stirring mayenhance the rate of the reaction. The reaction may conveniently becarried out at a temperature ranging between room temperature and refluxtemperature.

The final compounds of Formula (Ie) can be prepared by alkylation of afinal compound of Formula (I′) with compound of Formula (VIII) whereinW² in Formula (VIII) is an appropriate leaving group such as, forexample, a halogen, e.g. chloro or bromo, or a sulfonyloxy leavinggroup, e.g. methanesulfonyloxy or benzenesulfonyloxy. The reaction canbe performed in a reaction-inert solvent such as, for example, achlorinated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. ethanol,or a ketone, e.g. methyl isobutylketone, and in the presence of asuitable base such as, for example, sodium carbonate, sodium hydrogencarbonate or triethylamine. Stirring may enhance the rate of thereaction. The reaction may conveniently be carried out at a temperatureranging between room temperature and reflux temperature.

The final compounds of Formula (If) can be prepared by reductivelyN-alkylating an intermediate compound of Formula (I′) with anintermediate compound of Formula (IX). Said reductive N-alkylation maybe performed in a reaction-inert solvent such as, for example,dichloromethane, ethanol or toluene or a mixture thereof, and in thepresence of an appropriate reducing agent such as, for example, aborohydride, e.g. sodium borohydride, sodium cyanoborohydride ortriacetoxy borohydride. In case a borohydride is used as a reducingagent, it may be convenient to use a complex-forming agent such as, forexample, titanium(IV)isopropylate as described in J. Org. Chem, 1990,55, 2552-2554. It may also be convenient to use hydrogen as a reducingagent in combination with a suitable catalyst such as, for example,palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is usedas reducing agent, it may be advantageous to add a dehydrating agent tothe reaction mixture such as, for example, aluminium tert-butoxide. Inorder to prevent the undesired further hydro-genation of certainfunctional groups in the reactants and the reaction products, it mayalso be advantageous to add an appropriate catalyst-poison to thereaction mixture, e.g., thiophene or quinoline-sulphur. Stirring andoptionally elevated temperatures and/or pressure may enhance the rate ofthe reaction.

The final compounds of formula (Ig) are conveniently prepared by aBoronic Mannich reaction as described in Tetrahedron, 1997, 53,16463-16470; J. Am. Chem. Soc. 1998, 120, 11798-11799 or TetrahedronLetters, 2002, 43, 5965-5968 with an intermediate compound of Formula(I′) and intermediate compounds (X) and (XI) wherein Y in formula (X) isa bivalent radical of formula —CH₂— or >C(═O) and W³ in Formula (XI) ishydrogen or an alkyl chain. Said Boronic Mannich reaction may be reactedin the manner of a one-pot reaction with a carbohydrate or its dimer ofFormula (X) and an arylboronic acid or arylboronic ester of Formula (XI)in a reaction-inert solvent such as, for example, dichlomethane,ethanol, or 2,2,2-trifluoroethanol or a mixture thereof. Stirring mayenhance the rate of the reaction. The reaction may conveniently becarried out at a temperature ranging between room temperature and refluxtemperature.

The following examples are intended to illustrate but not to limit thescope of the present invention.

Experimental Part

Hereinafter “RT” means room temperature, “CDI” means1,1′-carbonyldiimidazole, “DIPE” means diisopropylether, “MIK” meansmethyl isobutyl keton, “BINAP” means[1,1′-binaphthalene]-2,2′-diylbis[diphenylphosphine], “NMP” means1-methyl-2-pyrrolidinone, “Pd₂(dba)₃” meanstris(dibenzylideneacetone)dipalladium, “DMF” meansN,N-dimethylformamide, “EDCI” means1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride and “HOBT”means hydroxybenzotriazole.

Preparation of the Intermediate Compounds

EXAMPLE A1

a. Preparation of Intermediate Compound 1

Et₃N (0.55 mol) was added to a stirring mixture of7-(phenylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane (0.5 mol) in toluene(1500 ml). 3,5-Bis(trifluoromethyl)benzoyl chloride (0.5 mol) was addedover a 1-hour period (exothermic reaction). The mixture was stirred atroom temperature for 2 hours, then allowed to stand for the weekend andwashed three times with water (500 ml, 2×250 ml). The organic layer wasseparated, dried, filtered and the solvent was evaporated. Yield: 245 g(100%). Crystallization of 2 gram of this fraction from petroleum etheryielded 1 g of intermediate compound 1. (50%).b. Preparation of Intermediate Compound 2

HCl cp (300 ml) was added to a mixture of intermediate compound 1 (0.5mol) in ethanol (300 ml) and H₂O (300 ml). The reaction mixture wasstirred at 60° C. for 20 hours. The precipitate was filtered off,ground, stirred in H₂O, filtered off, washed with petroleum ether anddried. Yield: 192 g of intermediate compound 2((±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinone)(89.4 %) (mixture of R and S enantiomers).c. Preparation of Intermediate Compound 3 and Intermediate Compound 4

Intermediate compound 2 was separated into its optical isomers by chiralcolumn chromatography over Chiralpak (CHIRALPAK AS 1000 Å 20 mm(DAICEL); eluent: hexane/2-propanol 70/30). Two product fractions werecollected and each solvent was evaporated. Yield Fraction 1: 32.6 g ofintermediate compound 3 (R), and Fraction 2: 30.4 g of intermediatecompound 4 (S).

EXAMPLE A2

a. Preparation of Intermediate Compound 5

A mixture of 1-(phenylmethyl)-4,4-piperidinediacetic acid hydrochloride(0.214 mol) and urea (0.149 mol) was stirred at 180° C. for 1 hour. EtOHand satured NaHCO₃ were added. The precipitate was filtered off anddried. EtOH was evaporated. The mixture was extracted with CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated. The residue (20 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1; 20-45 μm). Twofractions were collected and the solvent was evaporated. Yield: 4.4 g ofintermediate compound 5.a. Preparation of Intermediate Compound 6

LiAlH₄ (0.463 mol) was added portionwise at 5° C. to THF (400 ml).Intermediate compound 5 (0.077 mol) was added portionwise. The mixturewas stirred at 5° C. for 15 minutes, then brought to room temperatureand stirred and refluxed for 8 hours. Cold H₂O was added slowly. Themixture was filtered over celite. Celite was washed with CH₂Cl₂. Thefiltrate was extracted with CH₂Cl₂. The organic layer was separateddried (MgSO₄), filtered, and the solvent was evaporated. Yield: 13.7 gof intermediate compound 6 (72%).

EXAMPLE A3

a. Preparation of Intermediate Compound 7

Reaction under N₂ atmosphere. A mixture of(methoxymethyl)triphenylphosphonium chloride (0.0055 mol) andN-(1-methylethyl)-2-propanamine (0.0083 mol) in dry THF, p.a. (20 ml)was stirred at −70° C. 2.5 M BuLi/hexane (0.0055 mol) was addeddropwise. More 2.5 M BuLi/hexane (2.2 ml) was added. The mixture wasallowed to warm to room temperature. The reaction mixture was stirredfor 30 min at 20° C. The mixture was re-cooled to −25° C. A solution ofintermediate compound 3 (prepared according to A1.c) (0.005 mol) in somedry THF, p.a. was added dropwise and the reaction mixture was allowed towarm to room temperature. The reaction mixture was stirred overnight atroom temperature, then decomposed with water. The organic solvent wasevaporated and the aqueous concentrate was extracted with CH₂Cl₂. Theseparated organic layer was dried, filtered and the solvent evaporated.The residue was purified over silica gel (eluent: CH₂Cl₂). The desiredfractions were collected and the solvent was evaporated. Yield: 1.30 gintermediate compound 7 (57%).b. Preparation of Intermediate Compound 8

A mixture of intermediate compound 7 (0.0028 mol) in 1.6N HCl (6 ml) andTHF (6 ml) was stirred for one hour at 40° C. The THF was evaporated andthe aqueous concentrate was extracted with CH₂Cl₂. The separated organiclayer was washed with an aqueous Na₂CO₃ solution, dried, filtered andthe solvent evaporated. Yield: 1.24 g of intermediate compound 8 (100%,used in next reaction step, without further purification).c. Preparation of Intermediate Compound 9

A mixture of intermediate compound 8 (0.0081 mol) in CH₃CN (p.a.) (20ml) was stirred on an ice bath, giving mixture (I). A mixture of NaOCl₂(0.00975 mol) dissolved in H₂O (20 ml) was added dropwise at <10° C. tomixture (1). The reaction mixture was stirred for 2 hours at <10° C. andwas stirred overnight at room temperature. NaOH (25 ml, 10%) was addeddropwise to the mixture at room temperature and the reaction mixture waswashed with DEPE (2 times). The aqueous layer was acidified with HCl(10%) at <10° C., then extracted with CH₂Cl₂. The organic layer wasdried (MgSO₄) and filtered off. The solvent was evaporated and theresidue was crystallised from DIPE. Yield: 3.0 g of intermediatecompound 9 (80%).

EXAMPLE A4

a. Preparation of Intermediate Compound 10

A mixture of 2-[(3,4-dichlorophenyl)methyl]-4-oxo-1-piperidinecarboxylicacid ethyl ester (0.3 mol), 1,2-ethanediol (1.5 mol) and4-methylbezenesulfonic acid (2 g) in toluene (750 ml) was stirred andrefluxed for 68 hours using a water separator. The solvent wasevaporated. The residue was partitioned between water and toluene. Theorganic layer was separated, washed with water, dried, filtered and thesolvent evaporated. Yield: 113.5 g of intermediate compound 10.b. Preparation of Intermediate Compound 11

A mire of intermediate compound 10 (prepared according to A4.a) (0.1mol) and KOH (0.9 mol) in 2-propanol (500 ml) was stirred and refluxedovernight. The solvent was evaporated. The residue was dissolved inCH₂Cl₂ and then washed with a small amount of H₂O. The organic layer wasdried, filtered and the solvent was evaporated.

Yield: 33 g of intermediate compound 11.c. Preparation of Intermediate Compound 12 and 13

Intermediate compound 11 (prepared according to A4.b) (0.139 mol) wasdissolved in CH₂Cl (420 ml). 3,5-Bis(trifluoromethyl)benzoyl chloride(0.15 mol) was added dropwise. CH₂Cl₂ (30 ml) was added. The reactionmixture was stirred for 2 hours at room temperature. The reactionmixture was washed with 50% NaOH, with water, then dried, filtered andthe solvent evaporated. The residue was purified over silica gel (eluentgradient: CH₂Cl₂/CH₃OH from 100/0 to 95/5). The product fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom DIPE, filtered off and dried. Yield: 56.3 g of fraction 1. Thefiltrate was evaporated The residue was suspended in petroleum ether,filtered off and dried. Yield: 9 g of fraction 2. The fractions wereseparated and purified by chiral column chromatography (AD, 3-ginjections; eluent: heptane/ethanol 95/5). Two product fraction groupswere collected and their solvent was evaporated. Each residue wascrystallized from DIPE, filtered off and dried. Yield: 23.9 g ofintermediate compound 12 and 28.5 g of intermediate compound 13.d. Preparation of Intermediate Compound 14

A mixture of intermediate compound 12 (prepared according to A4.c)(0.0424 mol) in HCl (6N) (230 ml) was stirred and refluxed for 4 hours,then the reaction mixture was stirred overnight and extracted withCH₂Cl₂. The organic layer was separated, washed with water, dried andthe solvent was evaporated. Yield: 20 g of intermediate compound 14.

EXAMPLE A5

a. Preparation of Intermediate Compound 15

A solution of ethyl acetate (0.22 mol) in THF (200 ml) was added at −78°C. to a solution of nBuLi, 1.6M (0.178 mol) and diisopropylamine (0.1365mol) in THF (100 ml) under N₂ flow. The mixture was stirred for 30minutes. A solution of

(prepared according to the teachings in Helvetica Chimica Acta, (1972),55(7), p 2432-8 of which the content is included herein)) (0.105 mol) inTHF (300 ml) was added at −78° C. The mixture was stirred for 2 hours.H₂O was added. The mixture was extracted with EtOAc. The organic layerwas separated, dried (MgSO₄), filtered, and the solvent was evaporated.The residue (60 g) was purified by column chromatography over silica gel(eluent: cyclohexane/EtOAc 60/40). The pure fractions were collected andthe solvent was evaporated. Yield: 9.8 g intermediate compound 15 (25%).b. Preparation of Intermediate Compound 16

A mixture of intermediate compound 15 (0.026 mol) and LiCl(0.052 mol) inDMSO (100 ml) and H₂O (10 ml) was stirred at 200° C. for 2 hours. H₂Owas added. The mixture was extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated Theresidue (10 g) was purified by column chromatography over silica gel(eluent: cyclohexane/EtOAc 60/40; 15-40 μm). The pure fractions werecollected and the solvent was evaporated. Yield: 6.7 g of intermediatecompound 16 (86%).c. Preparation of Intermediate Compound 17

A mixture of intermediate compound 16 (0.022 mol) and NiRa (6.7 g) inCH₃OH (100 ml) was hydrogenated at room temperature overnight under a 3bar pressure, then filtered over celite. The filtrate was evaporated.The residue (7.5 g) was purified by column chromatography over silicagel (eluent gradient: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0 to 85/15/1). Yield 2.7 g(46%).d. Preparation of Intermediate Compound 18

A mixture of intermediate compound 17 (0.0104 mol) and Pd/C (0.3 g) inCH₃OH (30 ml) was hydrogenated at 50° C. overnight under a 4 barpressure, then filtered over celite. Celite was washed with CH₂Cl₂. Thefiltrate was evaporated Yield: 1.9 g of intermediate compound 18 (100%).

Preparation of the Final Compounds

EXAMPLE B1

a. Preparation of Final Compound 1

A mixture of intermediate compound 3 (prepared according to A1.c) (0.02mol), 3-(phenylmethyl)-3,9-diazaspiro-[5.5]-undecane (0.02 mol) andTi(iPrO)₄ (0.035 mol) in 1,2-dichloroethane (80 ml) was stirred at 50°C. for a overnight, then brought to room temperature under N₂ flow.NaBH(OAc)₃ (0.035 mol) was added portionwise. The mixture was stirred atroom temperature for 8 hours and poured out on ice. K₂CO₃ 10% was added.The mixture was filtered over celite and washed with CH₂Cl₂. Thefiltrate was extracted with CH₂Cl₂. The organic layer was separated,dried (MgSO₄), 10 filtered, and the solvent was evaporated. The residue(26 g) was purified by column chromatography over silica gel (eluentgradient: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5 to 90/10/1; 20-45 μm). Threefractions were collected and the solvent was evaporated.

Yield: 1.8 g of final compound 1 (15%).b. Preparation of Final Compound 5

A mixture of intermediate compound 3 (prepared according to A1.c) (0.033mol), 3-(phenylmethyl)-3,9-diazaspiro-[5.5]-undecane (0.033 mol),Ti(iPrO)₄ (0.036 mol) and Pd/C (1.5 g) in thiophene (1 ml) and methanol(150 ml) was hydrogenated at 50° C. for 18 hours under a 5 bar pressure,then filtered over celite. Celite was washed with CH₃OH. The filtratewas evaporated till dryness. The residue was dissolved in CH₂Cl₂. K₂CO₃10% was added. The mixture was stirred at room temperature for 30minutes, then filtered over celite. Celite was washed with CH₂Cl₂. Thefiltrate was extracted with CH₂Cl₂. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The residue (20g) was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NF₄OH 94/6/0.5; 20-45 μm). Two fractions were collected andthe solvent was evaporated. The residue was dissolved in iPrOH andconverted into the hydrochloric acid salt. The precipitate was filteredoff and dried.

Yield: 3.5 g of final compound 5 (14%) (melting point: 183° C.).c. Preparation of Final Compound 2

A mixture of final compound 1 (prepared according to B1.a) (0.001 mol)and Pd/C (0.1 g) in CH₃OH (6 ml) was hydrogenated at 40° C. for 48 hoursunder a 3 bar pressure, then filtered over celite. Celite was washedwith CH₃OH/CH₂Cl₂. The filtrate was evaporated. The residue (0.6 g) waspurified by column chromatography over silica gel (eluent gradient:CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.1 to 85/15/1; 35-70 μm). The pure fractionswere collected and the solvent was evaporated. Yield: 0.3 g of finalcompound 2 (58%).

EXAMPLE B2

Preparation of Final Compound 3

A mixture of final compound 2 (prepared according to B1.c) (0.0044 mol),cyclopropanecarboxylic acid (0.0052 mol), EDCI (0.0052 mol), HOBT(0.0058 mol) and Et₃N (0.0066 mol) in CH₂Cl₂ (25 ml) was stirred at roomtemperature for 24 hours, poured out into H₂O and extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue (3 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.2;15-40 μm). The pure fractions were collected and the solvent wasevaporated. The residue (1.8 g, 64%) was crystallized from diethylether. The precipitate was filtered off and dried. Yield: 1.45 g offinal compound 3 (51%) (melting point: 160° C.).

EXAMPLE B3

Preparation of Final Compound 4

A mixture of polystyrene-carbodiimide (1 eq) in CH₂Cl₂ (5 ml) wasstirred and cooled at 5° C. The acid (for the described example:alpha(hydroxymethyl)benzeneacetic acid) (1.5 eq) in CH₂Cl₂ (1 ml) wasadded and the mixture was stirred at room temperature for 30 minutes. Asolution of final compound 2 (prepared according to B1.c) in CH₂Cl₂ (2ml) was added and the mixture was stirred at 50° C. overnight. Thereaction mixture was filtered and the solvent evaporated. The residuewas purified by column chromatography over silica gel (Kromasil 5 μm,eluent gradient: CH₂Cl₂ 100 % to 95/5 CH₂Cl₂/MeOH). The pure fractionwas collected yielding 71% of the final compound 4.

EXAMPLE B4

Preparation of Final Compound 92

2-thiophenesulfonyl chloride (0.001 mol) was added portionwise at roomtemperature to a solution of final compound 2 (prepared according toB1.c) (0.001 mol) and Et₃N (0.001 mol) in CH₂Cl₂ (4 ml). The mixture wasstirred at room temperature for 48 hours. The organic layer was washedwith K₂CO₃ 10%, dried (MgSO₄), filtered, and the solvent was evaporated.The residue (0.45 g) was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1; 15-40 μm). The pure fractionswere collected and the solvent was evaporated This fraction wasdissolved in 2-propanone and converted into the ethanedioic acid salt.The precipitate was filtered off and dried. Yield: 0.28 g of compound 92(46%) (melting point: 132° C.).

EXAMPLE B5

Preparation of Final Compound 119

A mixture of final compound 2 (prepared according to B1.c) (0.176 mmol),4-cyanobenzenesulfonylchloride (1.4 eq) and polymer supported morpholine(1.5 eq) in CH₂Cl₂ (2 ml) was stirred at room temperature for 24 hours.Polymer supported tris(2-aminoethyl)amine polymer bond (1 eq) was added.The mixture was stirred at room temperature for 24 hours, filtered. Theresidue was purified by column chromatography over silica gel (Kromasil5 μm, eluent gradient: CH₂Cl₂ 100% to 95/5 CH₂Cl₂/MeOH). The purefraction was collected yielding 54% of the final compound 119.

EXAMPLE B6

Preparation of Final Compound 6

A mixture of final compound 1 (prepared according to B1.c) (0.001 mol),2-thienylboronic acid (0.01 mol) and glycolaldehyde dimer (0.001 mol) inethanol (5 ml) was stirred at room temperature for 18 hours. K₂CO₃ 10%was added. The mixture was extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue (0.6 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH/NH₄OH (95/5/0.1; 10 μm). The pure fractions werecollected and the solvent was evaporated. Yield: 0.238 g of finalcompound 6 (42%).

EXAMPLE B7

a) Preparation of Final Compound 130

A mixture of intermediate compound 14 (prepared according to A4.d)(0.0068 mol), 1,1-dimethylethyl-3,9-diazaspiro-[5,5]-undecane-3-carboxylic acid ester(0.0075 mol) and titanium(IV)isopropylate (0.0115 mol) in1,2-dichloroethane (50 ml) was stirred at 50° C. overnight. NaBH(OAc)₃(0.0115 mol) was added. The mixture was stirred at 50° C. for 1 hour.K₂CO₃ 10% and CH₂Cl₂ were added. The mixture was filtered over celite.The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue (6.3 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1;15-40 μm). Two fractions were collected and the solvent was evaporated.Yield: 0.8 g of final compound 130 (16%) (melting point: 80° C.).b) Preparation of Final Compound 129

A mixture of final compound 130 (prepared according to B7.a) (0.0011mol) in HCl in iPrOH (8 ml) and iPrOH (8 ml) was stirred at roomtemperature for 6 hours. H₂O was added. The mixture was basified withK₂CO₃ and extracted with CH₂Cl₂. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated till dryness. Yield:0.6 g of final compound 129 (86%).

EXAMPLE B8

a) Preparation of Final Compound 191

A mixture of intermediate compound 3 (prepared according to A1.c) (0.012mol), intermediate compound 18 (prepared according to A5.d)(0.011 mol),titanium(IV)isopropylate (0.012 mol) and thiophene (0.6 g) in Pd/C (0.5ml) and CH₃OH (100 ml) was hydrogenated at 50° C. under a 5 barpressure, then filtered over celite. The filtrate was evaporated. Theresidue was taken up in K₂CO₃ 10% and CH₂Cl₂. The mixture was filteredover celite. The filtrate was extracted with CH₂Cl₂. The organic layerwas separated, dried (MgSO₄), filtered, and the solvent was evaporated.The residue (6.6 g) was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 15-40 μm). Two fractions werecollected and the solvent was evaporated. Yield: 1.5 g (2R-cis) (24%)and 0.9 g (2R-trans) (14%).b) Preparation of Final Compound 195

NaH (0.0007 mol) was added at 5° C. to a mixture of final compound 191(0.0005 mol) in THF (2.5 ml) under N₂ flow. The mixture was stirred at50° C. for 30 minutes. A solution of (bromomethyl)cyclopropane (0.0005mol) in THF (2.5 ml) was added. The mixture was stirred at 60° C.overnight. H₂O was added. The mixture was extracted with EtOAc. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated. The residue (0.3 g) was purified by columnchromatography over kromasil (eluent gradient: CH₂Cl₂ 100 toCH₂Cl₂/CH₃OH/NH₄OH 90/10/0.5; 5 μm). The pure fractions were collectedand the solvent was evaporated. Yield: 0.23 g of final compound 195(70%).

EXAMPLE B9

Preparation of Final Compound 204

NaH was added at 5° C. to a solution of final compound 191 (preparedaccording to B8.a) in THF under N₂ flow. The mixture was stirred for 30minutes. 1-adamantyl bromomethyl ketone was added. The mixture wasstirred at 60° C. overnight.

Yield: 8 % of final compound 204.

EXAMPLE B10

Preparation of Final Compound 206

A mixture of intermediate compound 3 (prepared according to A1.c) (0.028mol),

(prepared according to the teachings in CAS180-50-7, J. Med. Chem. 1990,33, 2270-2275 of which the content is included herein) (0.028 mol),titanium(IV)isopropylate (0.033 mol) and Pd/C (1.5 g) in CH₃OH (150 ml)was hydrogenated at 50° C. for 18 hours under a 3 bar pressure, thenfiltered over celite. Celite was washed with CH₃OH. The filtrate wasevaporated till dryness. The residue was dissolved in cch. K₂CO₃ 10% wasadded. The mixture was stirred at room temperature for 1 hour, thenfiltered over celite. The filtrate was extracted with CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated Yield: 16 g of final compound 206 (100%). This productwas used directly in the next reaction step.

EXAMPLE B11

Preparation of Final Compound 212

A mixture of final compound 206 (prepared according to B10),3-furancarboxylic acid, PL-DCC (1.2 eq) and Et₃N (1.5 eq) in THF wasstirred in a sealed vessel at 100° C. in a microwaves (150 W) for 15minutes. Yield: 11% of final compound 212.

The following compounds were made according to one of the examplesabove. TABLE 1

Comp. Exp. stereo No. No. Alk^(a) Y Alk^(b) L descriptors 2 B1.c cb cbcb H 2R-trans 5 B1.a —CH₂— cb cb

2R-cis 1 B1.a —CH₂— cb cb

2R-trans 6 B6

cb cb

2R-trans 7 B2 cb C═O cb

2R-trans 8 B3 cb C═O cb

2R-cis 10 B3 cb C═O cb

2R-cis 3 B2 cb C═O cb

2R-trans 11 B3 cb C═O cb

2R-trans 12 B3 cb C═O cb

2R-trans 13 B3 cb C═O cb

2R-trans 14 B3 cb C═O cb

2R-trans 15 B3 cb C═O cb

2R-trans 16 B3 cb C═O cb

2R-trans 17 B3 cb C═O cb

2R-cis 18 B3 cb C═O cb

2R-cis 37 B3 cb C═O cb

2R-trans 38 B3 cb C═O cb

2R-cis 39 B3 cb C═O cb

2R-cis 40 B3 cb C═O cb

2R-trans 41 B3 cb C═O cb

2R-trans 19 B3 cb C═O cb

2R-trans 59 B3 cb C═O cb

2R-cis 60 B3 cb C═O cb

2R-trans 20 B3 cb C═O cb

2R-cis 21 B2 cb C═O cb

2R-trans; .oxalate 4 B2 +B3 cb C═O cb

2R-trans 22 B2 cb C═O cb

2R-trans 23 B3 cb C═O cb

2R-cis 24 B2 cb C═O cb

2R-trans; .oxalate 25 B3 cb C═O cb

2R-trans 26 B3 cb C═O cb

2R-cis 27 B3 cb C═O cb

2R-trans 28 B3 cb C═O cb

2R-cis 29 B3 cb C═O cb

2R-cis 30 B3 cb C═O cb

2R-trans 31 B3 cb C═O cb

2R-cis 32 B3 cb C═O cb

2R-trans 33 B3 cb C═O cb

2R-trans 34 B3 cb C═O cb

2R-trans 35 B3 cb C═O cb

2R-trans 36 B3 cb C═O cb

2R-trans 42 B3 cb C═O cb

2R-trans; .oxalate 43 B3 cb C═O cb

2R-trans 44 B3 cb C═O cb Error! Objects cannot be created from editingfield codes. 2R-trans 45 B3 cb C═O cb

2R-trans 46 B3 cb C═O cb

2R-trans 47 B3 cb C═O cb

2R-trans 48 B3 cb C═O cb

2R-trans 49 B3 cb C═O cb

2R-trans 50 B3 cb C═O cb

2R-trans 51 B3 cb C═O cb

2R-trans 52 B3 cb C═O cb

2R-trans 53 B3 cb C═O cb

2R-trans 54 B3 cb C═O cb

2R-cis 55 B3 cb C═O cb

2R-trans 56 B3 cb C═O cb

2R-cis 57 B3 cb C═O cb

2R-trans 58 B3 cb C═O cb

2R-trans 61 B3 cb C═O cb

2R-trans 62 B3 cb C═O cb

2R-trans 63 B3 cb C═O cb

2R-cis 64 B3 cb C═O cb

2R-trans 65 B3 cb C═O cb

2R-cis 66 B3 cb C═O cb

2R-trans 67 B3 cb C═O cb

2R-trans 68 B3 cb C═O cb

2R-trans 69 B3 cb C═O —CH₂—

2R-trans 70 B3 cb C═O —CH₂—

2R-trans 71 B3 cb C═O —CH₂—

2R-trans 72 B3 cb C═O —CH₂—

2R-trans 73 B3 cb C═O —CH₂—

2R-trans 74 B3 cb C═O —CH₂—

2R-trans 75 B3 cb C═O —CH₂—

2R-cis 76 B3 cb C═O —CH₂—

2R-trans 77 B3 cb C═O —CH₂—

2R-trans 78 B3 cb C═O —CH₂—

2R-trans 79 B3 cb C═O —CH₂—

2R-trans 80 B3 cb C═O —CH₂—

2R-trans 81 B3 cb C═O —CH₂—

2R-trans 82 B3 cb C═O —CH₂—

2R-trans 83 B3 cb C═O —CH₂—CH₂—

2R-trans 84 B3 cb C═O —CH═CH—

2R-trans 85 B3 cb C═O —CH═CH—

2R-trans 9 B3 cb C═O

H 2R-trans 86 B3 cb C═O

2R-trans 87 B3 cb C═O

2R-trans 88 B3 cb C═O

2R-trans 89 B3 cb C═O

2R-trans 90 B3 cb C═O

2R-trans 167 B5 cb

cb

2R-trans 91 B5 cb

cb

2R-trans 92 B4 cb

cb

2R-trans; .oxalate 93 B5 cb

cb

2R-trans 94 B5 cb

cb

2R-trans 95 B5 cb

cb

2R-trans 96 B5 cb

cb

2R-trans 97 B5 cb

cb

2R-trans 98 B5 cb

cb

2R-trans 99 B5 cb

cb

2R-trans 100 B5 cb

cb

2R-trans 101 B5 cb

cb

2R-trans 102 B5 cb

cb

2R-trans 103 B5 cb

cb

2R-trans 104 B5 cb

cb

2R-trans 105 B5 cb

cb

2R-trans 106 B5 cb

cb

2R-trans 107 B5 cb

cb

2R-trans 108 B5 cb

cb

2R-trans 109 B5 cb

cb

2R-trans 110 B5 cb

cb

2R-trans 111 B5 cb

cb

2R-trans 112 B5 cb

cb

2R-trans 113 B5 cb

cb

2R-trans 114 B5 cb

cb

2R-trans 115 B5 cb

cb

2R-trans 116 B5 cb

cb

2R-trans 117 B5 cb

cb

2R-trans 118 B5 cb

cb

2R-trans 119 B5 cb

cb

2R-trans 120 B5 cb

cb

2R-trans 121 B5 cb

cb

2R-trans 122 B5 cb

cb

2R-trans 123 B5 cb

cb

2R-trans 124 B5 cb

cb

2R-trans 125 B5 cb

cb

2R-trans 126 B5 cb

—CH₂—

2R-trans 127 B5 cb

—CH₂—

2R-trans 128 B5 cb

—CH═CH—

2R-transcb: covalent bond

TABLE 2

Comp. Exp. Physical No. No. R¹ Alk^(a) Y Alk^(b) L data 129 B2

cb cb cb H 2R-trans 130 B2

cb C═O cb

2R-trans 131 B2

cb C═O cb

2R-trans 132 B2

cb C═O cb

2R-trans 133 B2

cb C═O cb

2R-trans 134 B2

cb cb cb H 2R-trans 135 B2

—CH₂— cb cb

2R-trans 136 B2

cb C═O cb

2R-trans 137 B2

cb C═O cb

2R-trans 138 B2

cb C═O cb

2R-trans 139 B2

cb C═O cb

2R-trans 140 B2

cb C═O cb

2R-trans 141 B2

cb C═O cb

2R-transcb: covalent bond

TABLE 3

Comp. Exp. stereo No. No. R² descriptors 143 B3

2R-trans 144 B3

2R-trans 145 B3

2R-trans 162 B3

2R-trans 163 B3

2R-trans 146 B3

2R-trans 147 B3

2R-trans 148 B3

2R-trans 149 B3

2R-trans 150 B3

2R-trans 151 B3

2R-trans 152 B3

2R-trans 153 B3

2R-trans 154 B3

2R-trans 155 B3

2R-trans 156 B3

2R-trans 157 B3

2R-trans 158 B3

2R-trans 159 B3

2R-trans 160 B3

2R-trans 161 B3

2R-trans 164 B3

2R-trans 165 B3

2R-trans 166 B3

2R-trans

TABLE 4

Comp. Exp. stereo No. No. Alk^(a) Y Alk^(b) L descriptors 168 B1c cb cbcb H 2R-trans 169 B1c cb cb cb H 2R-cis 170 B1a —CH₂— cb cb

2R-trans 171 B1b —CH₂— cb cb

2R-cis 172 B2 cb C═O cb

2R-trans 173 B2 cb C═O cb

2R-cis 174 B2 cb C═O cb

2R-trans 175 B2 cb C═O cb

2R-trans 176 B2 cb C═O cb

2R-transcb: covalent bond

TABLE 5

Comp. Exp. stereo No. No. Z Alk^(a) Y Alk^(b) L descriptors 177 B1.c—CH₂— cb cb cb H 2S-trans 178 B10 —CH₂— —CH₂— cb cb

2S-trans 179 B2 —CH₂— cb C═O cb

2S-trans 180 B2 —CH₂— cb C═O cb

2S-trans 181 B2 —CH₂— cb C═O cb

2S-trans 182 B2 —CH₂— cb C═O cb

2S-trans 183 B2 —CH₂— cb C═O cb

2S-trans 184 B1.c C═O cb cb cb H 2S-trans 185 B9 C═O —CH₂— cb cb

2S-trans 186 B2 C═O cb C═O cb

2S-trans 187 B2 C═O cb C═O cb

2S-trans 188 B2 C═O cb CO cb

2S-trans 189 B2 C═O cb C═O cb

2S-trans 190 B2 C═O cb C═O cb

2S-transcb: covalent bond

TABLE 6

Comp. Exp. stereo No. No. Alk^(a) Y Alk^(b) L descriptors 191 B8.a cb cbcb H 2R-trans 192 B8.a cb cb cb H 2R-cis 193 B9 —CH₂— cb cb

2R-cis 194 B9 —CH₂— cb cb

2R-cis 195 B8.b —CH₂— cb cb

2R-trans 196 B8.b —CH₂— cb cb

2R-cis 197 B9 —CH₂— cb cb

2R-cis 198 B8.b —CH₂— cb cb

2R-cis 199 B8.b —CH₂— cb cb

2R-trans 200 B9 —CH₂— cb cb

2R-trans 201 B9 —CH₂— cb cb

2R-cis 202 B9 —CH₂— cb cb

2R-trans 203 B9 —CH₂— cb cb

2R-cis 204 B9 —CH₂— C═O cb

2R-trans 205 B9 —CH₂— C═O cb

2R-ciscb: covalent bond

TABLE 7

Comp. Exp. stereo No. No. Alk^(a) Y Alk^(b) L descriptors 206 B10 cb cbcb H 2R-trans 207 B11 cb C═O cb

2R-trans 208 B11 cb C═O cb

2R-trans 209 B11 cb C═O cb

2R-trans 210 B11 cb C═O cb

2R-trans 211 B11 cb C═O cb

2R-cis 212 B11 cb C═O cb

2R-trans 213 B11 cb C═O cb

2R-cis 214 B11 cb C═O cb

2R-trans 215 B11 cb C═O cb

2R-transcb: covalent: bondC. Analytical Data

For a number of compounds, either melting points or LCMS data wererecorded.

1. Melting Points

If possible, melting points (or ranges) were obtained with a Leica VMHBKoffler bank. The melting points are uncorrected. TABLE 8 Melting pointsfor selected compounds. Compound no. Result (° C.) 3 143 5 183 21 110 24132 36 125 42 162 92 132 130 80 131 90 132 110 133 109 136 160 137 100140 92 141 96 172 122 173 128 174 130 175 124 185 90 178 2202. LCMS Conditions

The HPLC gradient was supplied by a Waters Alliance HT 2795 system(Waters, Milford, Mass.) at room temperature. Flow from the column wassplit to a Waters 996 photodiode array (PDA) detector and a Waters-LCTmass spectrometer with an electrospray ionization source operated inpositive ionization mode. Reversed phase HPLC was carried out on aKromasil C18 column (5 μm, 4.6×150 mm) with a flow rate of 1 ml/min. Twomobile phases (mobile phase A: 100% 6.5 mM ammonium acetate+0.2% formicacid; mobile phase B: 100% acetonitrile) were employed to run a gradientcondition from 60% A & 40% B for 1 min to 100% B in 4 min., 100% B for 5min to 60% A & 40% B in 3 min, and re-equilibrate with 60% A & 40% B for3 min).

Mass spectra were acquired by scanning from 100 to 900 in 1 s using adwell time of 0.1 s. The capillary needle voltage was 3 kV and thesource temperature was maintained at 100° C. Nitrogen was used as thenebulizer gas. Cone voltage was 20 V for positive ionization mode. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem. TABLE 9 LCMS parent peak and retention time for selectedcompounds. Comp. LCMS Retention time no. MS(MH+) (min) 3 636 9.0 4 6793.8 5 658 3.4 6 694 2.9 7 652 4.9 8 652 5.0 9 664 4.9 10 636 4.6 11 6504.51 12 704 4.73 13 661 4.47 14 679 3.97 15 650 4.6 16 692 5.4 17 6645.1 18 664 5.0 19 690 5.0 20 666 4.3 21 666 4.2 22 679 4.0 23 662 4.6 24662 4.7 25 676 4.8 26 676 4.7 27 676 4.7 28 678 4.7 29 692 5.1 30 6925.3 31 692 5.0 32 692 4.9 33 675 4.6 34 676 3.9 35 691 4.5 36 694 4.8 37692 5.4 38 692 5.3 39 692 5.3 40 734 14.3 41 676 4.8 42 706 4.9 43 6974.7 44 737 5.2 45 678 4.5 46 690 4.3 47 718 4.4 48 691 8.2 49 673 4.3 50673 4.2 51 673 4.1 52 674 4.2 53 689 4.2 54 689 3.9 55 689 3.8 57 6894.0 58 692 4.1 59 730 5.9 60 730 5.8 61 748 5.3 62 716 4.8 63 716 5.1 64712 5.5 65 724 4.8 66 724 4.8 67 726 3.2 68 714 5.0 69 666 5.0 70 6765.0 71 692 5.2 72 744 6.0 73 719 4.4 74 730 5.6 75 692 4.8 76 692 4.8 77678 4.2 78 693 3.9 79 695 4.1 80 734 4.1 81 730 5.1 82 742 4.8 83 7305.2 84 688 5.2 85 688 4.9 86 704 5.1 87 712 5.2 88 716 4.6 89 712 5.0 90740 5.6 91 700 5.3 92 714 5.0 93 714 5.1 94 748 5.5 95 792 5.7 96 7826.0 97 782 5.8 98 870 6.0 99 860 6.0 100 726 4.4 101 727 5.2 102 708 5.2103 722 5.4 104 722 5.4 105 722 5.4 106 742 5.4 107 742 5.5 108 742 5.5109 776 5.6 110 776 5.7 111 776 5.5 112 776 5.8 113 776 5.8 114 776 5.8115 810 6.1 116 726 5.3 117 776 5.7 118 733 5.1 119 733 5.2 120 738 5.2121 738 5.3 122 768 5.0 123 768 5.2 124 765 4.8 125 786 <5 126 722 5.2127 756 5.4 128 734 5.4 130 736 5.7 131 704 5.0 132 734 4.8 133 746 5.2134 604.0 12.8 136 672 4.6 137 702 4.4 138 744 4.5 139 715 3.9 140 6984.7 141 714 4.8 143 490 3.7 144 503 2.4 145 506 2.2 146 528 3.7 147 5002.5 148 568 8.2 149 568 3.8 150 584 4.0 151 530 2.6 152 525 2.3 153 5283.7 154 568 3.8 155 568 8.7 156 536 3.3 157 650 4.8 158 560 4.0 159 5602.9 160 590 2.2 161 604 2.4 162 501 6.7 163 516 6.7 164 539 2.3 165 5503.8 166 551 2.9 167 674 4.9 170 658 6.1 172 636 4.7 173 636 4.8 174 6664.4 175 678 4.9 176 662 4.8 178 686 4.9 178 672 3.4 179 650 4.6 180 6804.3 181 779 <5 182 692 4.8 183 708 4.7 186 664 6.3 187 694 5.9 188 7936.6 189 706 6.4 190 722 6.3 192 582 3.94 193 638 4.76 194 666 5.23 195636 4.63 196 636 4.63 197 650 4.83 198 662 4.71 199 662 4.6 200 691 4.44201 691 4.54 202 690 4.9 203 690 5.03 204 758 5.7 205 758 5.87 207 6525.53 208 636 4.94 210 666 4.63 211 666 4.74 212 662 <5 213 662 5.1 214678 5.24 215 672 5.3

D. PHARMACOLOGICAL EXAMPLE EXAMPLE D.1 Binding Experiment for h-NK₁,h-NK₂ and h-NK₃ Receptors

The compounds according to the invention were investigated forinteraction with various neurotransmitter receptors, ion channels andtransporter binding sites using the radioligand binding technique.Membranes from tissue homogenates or from cells, expressing the receptoror transporter of interests, were incubated with a radioactivelylabelled substance ([³H]- or [¹²⁵I] ligand) to label a particularreceptor. Specific receptor binding of the radioligand was distinguishedfrom the non-specific membrane labelling by selectively inhibiting thereceptor labelling with an unlabelled drug (the blank), known to competewith the radioligand for binding to the receptor sites. Followingincubation, labelled membranes were harvested and rinsed with excessivecold buffer to remove non-bound radioactivity by rapid filtration undersuction. Membrane bound radioactivity was counted in a scintillationcounter and results were expressed in counts per minute (cpm).

The compounds were dissolved in DMSO and tested at 10 concentrationsranging from 10⁻¹⁰ to 10⁻⁵ M.

The ability of the compounds according to the invention to displace[³H]-Substance P from cloned human h-NK₁ receptors expressed in CHOcells, to displace [³H]-SR-48968 from cloned human h-NK₂ receptorsexpressed in Sf9 cells, and to displace [³H]-SR-142801 from cloned humanh-NK₃ receptors expressed in CHO cells was evaluated.

The receptor binding values (pIC₅₀) for the h-NK₁ ranges for allcompounds according to the invention between 10 and 6.

EXAMPLE D.2 Signal Transduction (ST)

This test evaluates in vitro functional NK₁ antagonistic activity. Forthe measurements of intracellular Ca⁺⁺ concentrations the cells weregrown on 96-well (black wall/transparent bottom) plates from Costar for2 days until they reached confluence. The cells were loaded with 2 μMFluo3 in DMEM containing 0.1% BSA and 2.5 mM probenecid for 1 h at 37°C. They were washed 3× with a Krebs buffer (140 mM NaCl, 1 mMMgCl₂×6H₂O, 5 mM KCl, 10 mM glucose, 5 mM HEPES; 1.25 mM CaCl₂; pH 7.4)containing 2.5 mM probenecid and 0.1% BSA (Ca⁺⁺-buffer). The cells werepreincubated with a concentration range of antagonists for 20 min at RTand Ca⁺⁺-signals after addition of the agonists were measured in aFluorescence Image Plate Reader (FLIPR from Molecular Devices, Crawley,England). The peak of the Ca⁺⁺-transient was considered as the relevantsignal and the mean values of corresponding wells were analysed asdescribed below.

The sigmoidal dose response curves were analysed by computerisedcurve-fitting, using the GraphPad Program. The EC₅₀-value of a compoundis the effective dose showing 50% of maximal effect. For mean curves theresponse to the agonist with the highest potency was normalised to 100%.For antagonist responses the IC₅₀ value was calculated using non-linearregression.

The pIC₅₀ data for the signal transduction testing for a representativeselection of compounds are presented in Table 10. The last columnsindicate—without being limited thereto—for which action the compoundsmight be most suitable. Of course, since for some neurokinin receptorsno data was determined, it is obvious that these compounds might beattributed to another suitable use. TABLE 10 Pharmacological data forthe signal transduction for selected compounds. NK₁ NK2 NK3 SuitableComp. No pIC₅₀ pIC50 pIC50 for 98 6.01 <5 <5 NK1 40 6.01 <5 <5 NK1 646.05 <5 <5 NK1 30 6.16 5.1 <5 NK1 203 6.18 5.47 <5 NK1 212 6.20 5.455.42 NK1 207 6.23 5.72 5.24 NK1 99 6.25 <5 <5 NK1 128 6.25 5.27 <5 NK1112 6.26 <5 <5 NK1 201 6.66 5.55 ˜5 NK1 115 6.31 <5 <5 NK1 96 6.33 5.9˜5 NK1 117 6.35 <5 <5 NK1 63 6.36 5.1 <5 NK1 63 6.36 5.1 <5 NK1 178 6.365.31 <5 NK1 113 6.37 <5 <5 NK1 74 6.41 <5 <5 NK1 87 6.41 5.22 <5 NK1 1146.44 <5 <5 NK1 90 6.45 5.27 <5 NK1 59 6.46 <5 5.23 NK1 208 6.46 5.585.37 NK1 198 6.47 5.32 <5 NK1 72 6.49 <5 <5 NK1 108 6.49 5.58 5.4 NK1 856.51 <5 <5 NK1 68 6.53 5.25 <5 NK1 84 6.55 5.14 <5 NK1 211 6.55 5.34 ˜5NK1 78 6.57 <5 <5 NK1 95 6.57 5.72 5.63 NK1 61 6.58 <5 <5 NK1 127 6.585.33 <5 NK1 202 6.61 5.34 5.14 NK1 60 6.62 5.33 5.33 NK1 193 6.62 5.65.24 NK1 48 6.66 <5 <5 NK1 196 6.67 5.19 ˜5.51 NK1 33 6.70 <5 <5 NK1 166.72 <5 5.07 NK1 34 6.72 5.21 <5 NK1 197 6.72 5.54 5.19 NK1 62 6.73 <5<5 NK1 110 6.76 n.d. 5.29 NK1 79 6.77 <5 <5 NK1 44 6.79 5.35 5.34 NK1155 6.80 5.19 n.d. NK1 125 6.80 5.29 5.16 NK1 55 6.80 5.4 <5 NK1 57 6.825.72 <5 NK1 41 6.83 5.07 <5 NK1 41 6.83 5.07 <5 NK1 89 6.83 5.6 <5 NK1153 6.84 <5 n.d. NK1 53 6.86 <5 <5 NK1 86 6.89 <5 <5 NK1 6 6.89 5.11 <5NK1 15 6.89 5.5 5.10 NK1 7 6.94 <5 <5 NK1 81 6.94 5.28 <5 NK1 107 6.945.38 5.50 NK1 9 6.97 <5 <5 NK1 49 6.97 5.40 <5 NK1 46 6.98 5.20 <5 NK111 6.98 5.27 n.d. NK1 43 6.98 5.44 <5 NK1 37 7.02 5.09 <5 NK1 37 7.025.09 <5 NK1 71 7.03 5.01 <5 NK1 71 7.03 5.01 <5 NK1 172 7.03 5.16 5.24NK1 91 7.06 5.86 5.36 NK1 97 7.06 n.d. ˜5 NK1 39 7.07 5.32 5.27 NK1 257.08 5.40 <5 NK1 185 7.09 5.26 <5 NK1 70 7.09 5.27 <5 NK1 45 7.10 5.27<5 NK1 50 7.11 5.58 <5 NK1 32 7.12 5.50 5.18 NK1 176 7.14 ˜5.19 <5 NK1123 7.15 ˜5.39 <5 NK1 47 7.18 ˜5 <5 NK1 66 7.18 5.43 5.16 NK1 58 7.19 <5<5 NK1 69 7.19 5.51 5.18 NK1 42 7.21 5.05 5.03 NK1 42 7.21 5.05 5.03 NK152 7.22 5.54 <5 NK1 179 7.23 <5 <5 NK1 67 7.24 5.01 <5 NK1 67 7.24 5.01<5 NK1 133 7.27 5.43 5.31 NK1 101 7.31 5.70 5.22 NK1 82 7.33 5.70 5.05NK1 77 7.34 ˜5.09 <5 NK1 77 7.34 ˜5.09 <5 NK1 122 7.35 5.40 <5 NK1 87.36 5.55 5.35 NK1 141 7.38 5.23 5.15 NK1 88 7.38 5.52 <5 NK1 174 7.395.16 <5 NK1 182 7.42 <5 5.04 NK1 182 7.42 <5 5.04 NK1 182 7.42 <5 5.04NK1 83 7.44 5.59 5.05 NK1 22 7.44 5.75 <5 NK1 181 7.47 5.15 <5 NK1 737.48 <5 <5 NK1 73 7.48 <5 <5 NK1 73 7.48 <5 <5 NK1 126 7.48 5.47 5.4 NK114 7.50 <5 n.d. NK1 14 7.50 <5 n.d. NK1 14 7.50 <5 n.d. NK1 173 7.51˜5.79 <5 NK1 80 7.53 <5 <5 NK1 80 7.53 <5 <5 NK1 51 7.53 5.44 <5 NK1 1897.54 5.17 <5 NK1 36 7.55 5.37 <5 NK1 140 7.63 5.46 5.61 NK1 27 7.69 5.355.48 NK1 187 7.7 5.15 <5 NK1 35 7.72 <5 <5 NK1 35 7.72 <5 <5 NK1 1387.75 5.33 <5 NK1 183 7.77 5.11 5.13 NK1 186 7.77 5.30 5.27 NK1 21 7.785.63 5.67 NK1 175 7.81 5.35 <5 NK1 188 7.82 5.26 5.43 NK1 180 7.83 5.08<5 NK1 111 6.69 ˜6.64 5.27 NK1-2 121 6.95 5.92 5.43 NK1-2 76 7.59 5.945.40 NK1-2 200 7.63 5.84 5.16 NK1-2 18 7.69 5.92 5.33 NK1-2 190 8.215.79 5.45 NK1-2 210 6.54 5.74 5.75 NK1-3 94 6.88 <5 6.24 NK1-3 24 6.95<5 5.88 NK1-3 105 6.98 5.61 5.70 NK1-3 104 7.19 ˜5.34 5.71 NK1-3 1027.21 <5 6.15 NK1-3 106 7.22 5 6.28 NK1-3 167 7.25 5.69 5.71 NK1-3 1167.28 <5 6.15 NK1-3 103 7.30 5.60 5.82 NK1-3 139 7.41 5.62 6.02 NK1-3 1997.43 5.56 6.07 NK1-3 118 7.51 n.d. 5.82 NK1-3 137 7.56 5.46 5.77 NK1-3124 7.63 ˜5.59 5.75 NK1-3 136 7.77 5.70 6.16 NK1-3 119 7.18 5.97 5.8NK1-2-3 195 7.27 ˜5.85 5.84 NK1-2-3 4 7.41 5.81 5.89 NK1-2-3 3 7.43 5.965.82 NK1-2-3 93 7.59 5.96 6.30 NK1-2-3 131 7.76 6.11 5.85 NK1-2-3 927.77 5.88 6.47 NK1-2-3 100 7.92 5.9 6.48 NK1-2-3 132 8.02 5.77 6.04NK1-2-3(n.d. = not determined)

E. COMPOSITION EXAMPLES

“Active ingredient” (A.I.) as used throughout these examples relates toa compound of Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof, theN-oxide form thereof and prodrugs thereof.

EXAMPLE E.1 Oral Drops

500 Grams of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acidand 1.5 l of the polyethylene glycol at 60˜80° C. After cooling to30˜40° C. there were added 35 l of polyethylene glycol and the mixturewas stirred well. Then there was added a solution of 1750 grams ofsodium saccharin in 2.5 l of purified water and while stirring therewere added 2.5 l of cocoa flavor and polyethylene glycol q.s. to avolume of 50 l, providing an oral drop solution comprising 10 mg/ml ofA.I. The resulting solution was filled into suitable containers.

EXAMPLE E.2 Oral Solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3l of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

EXAMPLE E.3 Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about200 ml of water. The wet powder mixture was sieved, dried and sievedagain. Then there was added 100 grams microcrystalline cellulose and 15grams hydrogenated vegetable oil. The whole was mixed well andcompressed into tablets, giving 10,000 tablets, each containing 10 mg ofthe active ingredient.

To a solution of 10 grams methyl cellulose in 75 ml of denaturatedethanol there was added a solution of 5 grams of ethyl cellulose in 150ml of dichloromethane. Then there were added 75 ml of dichloromethaneand 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol wasmolten and dissolved in 75 ml of dichloromethane. The latter solutionwas added to the former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentratedcolor suspension and the whole was homogenated. The tablet cores werecoated with the thus obtained in a coating apparatus.

EXAMPLE E.4 Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 l of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I.The solution was sterilized by filtration and filled in sterilecontainers.

1. A compound according to the general Formula (I)

the pharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof, the N-oxide form thereof andprodrugs thereof, wherein: R² is Ar², Ar²-alkyl, di(Ar²)alkyl, Het¹ orHet¹-alkyl; X is a covalent bond or a bivalent radical of formula —O—,—S— or —NR³—; Q is O or NR³; each R³ independently from each other, ishydrogen or alkyl; R¹ is selected from the group of Ar¹, Ar¹-alkyl anddi(Ar¹)-alkyl; n is an integer, equal to 0, 1 or 2 m is an integer,equal to 1 or 2, provided that if m is 2, then n is 1; Z is a covalentbond or a bivalent radical of formula —CH₂— or >C(═O); j, k, p, q areintegers, independently from each other equal to 0, 1, 2, 3 or 4;provided that (j+k) and (p+q) are equal to 4; T is ═O in analpha-position relative to the N-atom and t is an integer, equal to 0 or1; each Alk represents, independently from each other, a covalent bond;a bivalent straight or branched, saturated or unsaturated hydrocarbonradical having from 1 to 6 carbon atoms; or a cyclic saturated orunsaturated hydrocarbon radical having from 3 to 6 carbon atoms; eachradical optionally substituted on one or more carbon atoms with one ormore, phenyl, halo, cyano, hydroxy, formyl and amino radicals; Y is acovalent bond or a bivalent radical of formula —C(═O)—, —SO₂— >C═CH—Ror >C═N—R, wherein R is H, CN or nitro; L is selected from the group ofhydrogen, alkyl, alkenyl, alkyloxy, alkyloxyalkyloxy, alkylcarbonyloxy,alkyloxycarbonyl, mono- and di(alkyl)amino, mono- anddi(alkyloxycarbonyl)amino, mono- and di(alkylcarbonyl)amino, mono- anddi(Ar³)amino, mono- and di(Ar³ alkyl)-amino, mono-and di(Het²)amino,mono-and di(Het²alkyl)amino, alkylsulfanyl, norbornyl, adamantyl,tricycloundecyl, Ar³, Ar³-oxy, Ar³carbonyl, Het², Het-oxy, Het²carbonyland mono- and di(Het²carbonyl)amino; Ar¹ is phenyl, optionallysubstituted with 1, 2 or 3 substituents, each independently from eachother, selected from the group of halo, alkyl, cyano, aminocarbonyl andalkyloxy; Ar² is naphthalenyl or phenyl, each optionally substitutedwith 1, 2 or 3 substituents, each independently from each other,selected from the group of halo, nitro, amino, mono- and di(alkyl)amino,cyano, alkyl, hydroxy, alkyloxy, carboxyl, alkyloxycarbonyl,aminocarbonyl and mono- and di(alkyl)aminocarbonyl; Ar³ is naphthalenylor phenyl, optionally substituted with 1, 2 or 3 substituents, eachindependently from each other, selected from the group of alkyloxy,alkylcarbonylamino, methanesulfonyl, Ar¹carbonyloxyalkyl,Ar¹alkyloxycarbonyl, Ar¹alkyloxyalkyl, alkyl, halo, hydroxy, pyridinyl,morpholinyl, pyrrolyl, pyrrolidinyl, imidazo[1,2-a]pyridinyl,morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano; Het¹ is amonocyclic heterocyclic radical selected from the the group of pyrrolyl,pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl; or a bicyclic heterocyclic radical selected from the groupof quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl,benzothienyl, indanyl and chromenyl; wherein each mono- and bicyclicheterocyclic radical may optionally be substituted on any atom by one ormore radicals, each independently from each other, selected from thegroup of halo, oxo and alkyl; Het² is a monocyclic heterocyclic radicalselected from the group of pyrrolidinyl, dihydro-2H-pyranyl, pyranyl,dioxolyl, imidazolidinyl, tetrahydropyridinyl, tetrahydropyrimidinyl,pyrazolidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, imidazolidinyl, tetrahydrofuranyl, 2H-pyrrolyl, pyrrolinyl,imidazolinyl, pyrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,furanyl, thienyl, oxazolyl, dioxazolyl, oxazolidinyl, isoxazolyl,thiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, 1H-pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl and tetrazolyl; or abicyclic heterocyclic radical selected from the group of2,3-dihydro-benzo[1,4]dioxine, octahydro-benzo[1,4]dioxine,octabicycloheptyl, benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl,isoindolyl, chromanyl, benzimidazolyl, imidazo[1,2-a]pyridinyl,benzoxazolyl, benzodioxolyl, benzisoxazolyl, benzoxadiazolyl,benzothiazolyl, benzisothiazolyl, benzofuranyl, dihydroisobenzofuranyl,or benzothienyl; wherein each mono-, and bicyclic heterocyclic radicalmay optionally be substituted on any atom with one or more radicalsselected from the group of Ar¹, Ar¹alkyl, Ar¹alkyloxyalkyl, halo,hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo, alkyloxy,alkylcarbonyl, Ar¹carbonyl, mono- and di(alkyl)aminoalkyl, alkyloxyalkyland alkyloxycarbonyl; alkyl is a straight or branched saturatedhydrocarbon radical having from 1 to 6 carbon atoms or a cyclicsaturated hydrocarbon radicals having from 3 to 6 carbon atoms; eachhydrocarbon radical optionally substituted on one or more carbon atomswith one or more radicals selected from the group of phenyl, halo,trihalomethyl, aminocarbonyl, methyl, ethyl, propyl, isopropyl, t-butyl,cyano, oxo, hydroxy, formyl and amino; and alkenyl is a straight orbranched unsaturated hydrocarbon radical having from 1 to 6 carbon atomsand having 1 or more unsaturated bonds; or a cyclic unsaturatedhydrocarbon radical having from 3 to 6 carbon atoms and having 1 or moreunsaturated bonds; each hydrocarbon radical optionally substituted onone or more carbon atoms with one or more radicals selected from thegroup of phenyl, halo, cyano, oxo, hydroxy, formyl and amino.
 2. Acompound according to claim 1 wherein: R² is Ar², Ar²-alkyl or Het¹; Xis a covalent bond; Q is O; R¹ is Ar¹-alkyl; n is an integer, equal to1; m is an integer, equal to 1; Z is a covalent bond or a bivalentradical of formula —CH₂— or >C(═O); j, k, p, q are integers,independently from each other equal to 1, 2 or 3; provided that each of(j+k) and (p+q) is equal to 4; t is an integer, equal to 0 or 1; eachAlk represents, independently from each other, a covalent bond; abivalent straight or branched, saturated or unsaturated hydrocarbonradical having from 1 to 6 carbon atoms; or a cyclic saturated orunsaturated hydrocarbon radical having from 3 to 6 carbon atoms; eachradical optionally substituted with an hydroxy radical; Y is a covalentbond or a bivalent radical of formula —C(═O)— or —SO₂—; L is selectedfrom the group of hydrogen, alkyl, alkenyl, alkyloxy, norbornyl,tricycloundecyl, Ar³, Ar³-oxy, Het² and mono- and di(Het²carbonyl)amino;Ar¹ is phenyl, optionally substituted with 2 halo-radicals; Ar² isnaphthalenyl or phenyl, each optionally substituted with 1, 2 or 3substituents, each independently from each other, selected from thegroup of halo, cyano, alkyl and alkyloxy; Ar³ is phenyl, optionallysubstituted with 1 substituent, selected from the group of alkyloxy,alkylcarbonylamino, methanesulfonyl, alkyl, halo, pyrrolyl and cyano;Het¹ is a monocyclic heterocyclic radical selected from the the group ofpyrrolyl, furanyl, thienyl, pyridinyl and pyrazinyl; or a bicyclicheterocyclic radical selected from the group of quinolinyl and indolyl;wherein each mono- and bicyclic heterocyclic radical may optionally besubstituted on any atom by one or more alkyl radicals; Het² is amonocyclic heterocyclic radical selected from the group of pyrrolidinyl,dihydro-2H-pyranyl, pyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,pyrrolyl, imidazolyl, furanyl, thienyl, oxazolidinyl, isoxazolyl,thiadiazolyl, pyridinyl, 1H-pyridinyl, pyrazinyl, pyridazinyl andtetrazolyl; or a bicyclic heterocyclic radical selected from the groupof octabicycloheptyl, quinoxalinyl, benzimidazolyl, benzodioxolyl,benzoxadiazolyl, benzofuranyl or dihydroisobenzofuranyl; wherein eachmono- and bicyclic heterocyclic radical may optionally be substituted onany atom with one or more radicals selected from the group of halo,alkyl, oxo and alkyloxycarbonyl; alkyl is a straight or branchedsaturated hydrocarbon radical having from 1 to 6 carbon atoms or acyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms;each hydrocarbon radical optionally substituted on one or more carbonatoms with one or more radicals selected from the group oftrihalomethyl, aminocarbonyl, methyl, t-butyl and cyano; and alkenyl isa cyclic unsaturated hydrocarbon radical having from 3 to 6 carbon atomsand having 1 unsaturated bond.
 3. A compound according to claim 1wherein R¹ is Ar¹ methyl and attached to the 2-position or R¹ is Ar¹ andattached to the 3-position.
 4. A compound according to, claim 1 whereinthe spiro-moiety has the Formula (f1), (f2) or (f12), wherein thevariables are defined as in Formula (I) and “a” denotes thepiperidinyl-moiety of Formula (I) and “b” denotes the Alk-Y-Alk-L-moietyof Formula (I).


5. A compound according to, claim 1 wherein the R²—X—C(=Q)- moiety is3,5-di-(trifluoromethyl)phenylcarbonyl.
 6. A compound according to,claim 1 wherein m and n are both equal to
 1. 7. A compound according to,claim 1 wherein Y is —C(═O)—.
 8. A compound according to, claim 1wherein Alk is a covalent bond or —CH₂—.
 9. A compound according to,claim 1 wherein L is cyclopropyl.
 10. A compound selected from the groupof compounds with compound number 132, 100, 92, 93, 3, 4 and
 119. 11. Acompound according to claim 1 for use as a medicine.
 12. (canceled) 13.A method for treating tachykinin mediated conditions comprisingadministering to a patient in a need of treatment a therapeuticallyeffective amount of a compound according to claim
 1. 14. A method fortreating a patient in need of treatment and/or prophylaxis ofschizophrenia, emesis, anxiety and depression, irritable bowel syndrome(IBS), circadian rhythm disturbances, pre-eclampsia, nociception, pain,in particular visceral and neuropathic pain, pancreatitis, neurogenicinflammation, asthma, COPD and micturition disorders comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 to said patient in need of treatment.
 15. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and, asactive ingredient, a therapeutically effective amount of a compoundaccording to claim
 1. 16. A process for preparing a pharmaceuticalcomposition as claimed in claim 15, characterized in that apharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of a compound as claimed in claims 1.17. Process for preparing a compound according to Formula (I)characterized by either a) reductively N-alkylating an intermediatecompound of Formula (II) with an intermediate compound of Formula (III)to obtain a final compound according to Formula (Ia), wherein allvariables are defined as in claim 1, in a reaction-inert solvent andoptionally in the presence of an appropriate reducing agent; or

b) reductively N-alkylating an intermediate compound of Formula (IV)with an intermediate compound of Formula (III) to obtain a finalcompound according to Formula (Ib), wherein all variables are defined asin claim 1, in a reaction-inert solvent and optionally in the presenceof an appropriate reducing agent; or

c) reacting an intermediate compound of Formula (III) with a carboxylicacid compound of Formula (V) to obtain a final compound according toFormula (Ic), wherein all variables are defined as in claim 1, in areaction-inert solvent and optionally in the presence of a suitablebase; and

(d) optionally, converting compounds of Formula (I), in particularFormula (Ia), (Ib) and (Ic) into each other by transformations, andfurther, optionally, converting the compounds of Formula (I), into atherapeutically active non-toxic acid addition salt by treatment with anacid, or into a therapeutically active non-toxic base addition salt bytreatment with a base, or conversely, converting the acid addition saltform into the free base by treatment with alkali, or converting the baseaddition salt into the free acid by treatment with acid; and, ifdesired, preparing stereochemically isomeric forms, N-oxides thereof andquaternary ammonium salts thereof.
 18. Process according to claim 17,wherein the Alk-Y-Alk-L-moiety in the compounds of Formulas (III), (Ia),(Ib) and (Ic) is benzyl.